De novo construction of C–O axial chirality via cobalt-catalyzed atroposelective C–H activation/annulation

Abstract

The catalytic asymmetric synthesis of axially chiral compounds has attracted growing attention over the past decades. C–O axially chiral compounds represent a distinctive class of atropisomers characterized by a unique dual-axial architecture. Their atroposelective construction remains a formidable challenge due to inherent low rotational barriers and high conformational flexibility. Current catalytic approaches rely predominantly on enantioselective desymmetrization of preformed diaryl ethers. Here, we report an unprecedented de novo synthetic strategy, enabling the construction of a new class of C–O axially chiral aryl-heterocyclic ethers. This protocol is achieved by an earth-abundant cobalt-catalyzed atroposelective C–H activation/annulation of arylamides with phenylethynyl ethers, which concurrently builds the heterocycle and the C–O chiral axis in a single step. Notably, a traceless directing group strategy is successfully implemented, featuring smooth in situ cleavage. Furthermore, a series of C–O atropisomers bearing multiple stereogenic elements are prepared with excellent stereoselectivity. Racemization experiments reveal high configurational stability of the products. Derivatization studies afford a versatile library of non-biaryl C–O axially chiral scaffolds, extending the applicability of this strategy.

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Introduction

Developing efficient strategies for the construction of diverse chiral entities has long been a central pursuit in chemical research.^1–10 In contrast to the extensively studied point chirality, axial chirality arises from restricted rotation around a stereogenic axis. Given the widespread application of atropisomeric frameworks in pharmaceuticals and advanced materials, substantial efforts have been devoted to their asymmetric construction. Distinct from well-established mono-axial chiral systems (Fig. 1a), such as C–C, C–N, C–B, and N–N atropisomers, the distinctive C–O axially chiral architecture features a unique dual-axial chirality,^11–15 wherein two contiguous C–O axes are bonded to a central oxygen atom. This structural motif is not only prevalent in bioactive molecules and natural products,^16–23 but also serves as a privileged scaffold in functional molecules²⁴ and phosphine ligands^25–28 (Fig. 1b). Despite their significance, the asymmetric construction of C–O atropisomers remains largely underdeveloped, and is hindered by several intrinsic challenges: (1) the inherently low rotational barriers associated with two contiguous C–O axes endow C–O axially chiral compounds with flexible atropisomerism,²⁹ triggering facile racemization via concerted rotation of both axes; (2) simultaneous stereocontrol over two C–O axes complicates the achievement of high atroposelectivity compared to mono-axial chirality molecules; (3) the oxygen bridge between the two C–O axes weakens spatial and electronic interactions of substituents, resulting in enhanced conformational freedom. Consequently, these factors collectively compromise the configurational stability and synthetic accessibility of dual-axial scaffolds, making their catalytic asymmetric synthesis a considerable challenge.

Fig. 1 Background and project synopsis for the synthesis of C–O atropisomers. (a) Axially chiral skeletons and synthetic challenges in C–O axially chiral compounds. (b) Selected bioactive molecule and ligand featuring C–O axis. (c) Previous catalytic strategies for synthesizing C–O atropisomers. (d) This work: de novo construction of C–O axially chiral aryl-isoquinolinol ethers via cobalt-catalyzed C–H activation/annulation.

Since the pioneering investigations of C–O atropisomers by Fuji,³⁰ the catalytic asymmetric construction of such architectures has gained growing attention in the synthetic community and represents a significant frontier in modern stereochemistry.^{11–15,31,32} Several elegant catalytic enantioselective approaches toward C–O atropisomers have been achieved (Fig. 1c). However, current strategies rely mostly on atroposelective desymmetrization via enzymatic,^33,34 organocatalytic^35–43 or transition-metal-catalyzed functionalizations,^44–48 and focus predominantly on the synthesis of C–O axially chiral diaryl ether frameworks. The exclusive construction of axially chiral naphthoquinone-aryl ethers was achieved by Gustafson via a dynamic kinetic resolution approach.⁴⁹ Given the significance of privileged C–O axial structures, it is highly desirable to develop novel synthetic strategies that could enable the efficient construction of C–O atropisomers with broader structural diversity.

Over the past decades, the transition-metal catalyzed^50–53 asymmetric C–H activation has emerged as an atom-economical and versatile platform for accessing enantiopure molecules. However, forging C–O axially chiral compounds via this versatile approach has not been realized to date. More recently, the 3d-metal cobalt-catalyzed asymmetric C–H activation^53–58 has attracted considerable attention since the independent establishment of cobalt/salicyloxazoline (Salox) catalytic system by the Shi group⁵⁹ and our group.⁶⁰ This 3d-metal platform has enabled facile access to diverse axially chiral architectures, including C–C, C–N, and N–N atropisomers.^60–79 Inspired by these achievements, we hypothesized that the cobalt/Salox catalysis could offer a promising solution for synthesizing C–O atropisomers.

Herein, we report an unprecedented de novo synthetic strategy, delivering a new type of C–O axially chiral aryl-heterocyclic ethers that differ from the previously reported diaryl ether compounds (Fig. 1d). This protocol is successfully implemented through a cobalt-catalyzed atroposelective C–H activation/annulation of benzamides with rationally designed phenylethynyl ethers. The simultaneous construction of both the isoquinolinone heterocycle and the C–O chiral axis is faciliated in a single synthetic step. Notably, a traceless directing group approach is achieved using 2-(1-methylhydrazinyl)pyridine, which is cleaved in situ during the reaction. Meanwhile, a diverse array of C–O axially chiral compounds bearing multiple stereogenic elements are obtained with high stereoselectivity via the smoothly synchronous modulation of remote C–O and C–N axes. Moreover, high configurational stability is identified for the prepared C–O atropisomers through racemization studies. X-ray crystallography reveals a non-covalent π–π interaction between the isoquinolinone ring and the phenyl substituent of the phenylethynyl ether, likely contributing to both stereocontrol and the configurational stabilization of obtained products.

Results and discussion

Optimizing reaction conditions

We began the investigations by subjecting phenylethynyl ether 1a and benzamide 2a preinstalled with 2-(1-methylhydrazinyl)pyridine^74,80–83 as directing group to the cooperative Co/Salox catalytic system. Initially, various chiral Salox ligands were evaluated in combination with Co(OAc)₂·4H₂O as catalyst, Mn(OAc)₂·4H₂O as oxidant in 2-BuOH (0.1 M) at 60 °C for 10 h under air atmosphere (Table 1). Gratifyingly, the desired product 3a could be obtained in 91% yield with 75% ee in the presence of L1, and the directing group could be removed in situ during the transformation. Then the steric and electronic influence of substituents on the ligand were examined. The ortho-substituted L2, L3 and L4 afforded 3a with improved enantioselectivities (85%, 95%, and 90% ee, respectively), and the yields remained low (56%, 17%, and 23%, respectively). Introducing para-substituents (L5, L6, L7) had negligible effect on the stereoselectivity of this reaction. Notably, a superior result was obtained in the presence of L8, which features ortho- and para-isopropyl substituted phenol moiety, delivering 3a in 46% yield with 96% ee. The more sterically bulky L9 and L10 gave only trace amount of product. Subsequently, other reaction parameters, including cobalt salts, solvents, reaction temperature, and dosages of cobalt, ligand, and oxidants, were systematically optimized (Table 1 and S1–S9 in the SI). The best performance was attained under the conditions as shown in entry 15: Co(OAc)₂·4H₂O (10 mol%) as catalyst, L8 (20 mol%) as ligand, Mn(OAc)₂·4H₂O (0.5 equiv.) as co-oxidant, in 2-BuOH at 60 °C under air atmosphere, and the desired product 3a was obtained in 89% yield with 96% ee. Moreover, the use of other directing groups, such as 2-(1-ethylhydrazinyl)pyridine, 2-(1-propylhydrazinyl)pyridine, and 2-(1-benzylhydrazinyl)pyridine (Table S10), also afforded product 3a (81%, 96% ee; 77%, 96% ee; 18%, 96% ee, respectively).

Table 1 Optimization studies

Entry^a	[Co]	[Mn] (x equiv.)	Solvent	T (°C)	t (h)	Yield (%)	ee (%)
a Reaction conditions: 1a (0.12 mmol), 2a (0.1 mmol), cobalt catalyst (10 mol%), ligand (20 mol%), Mn(OAc)2·4H2O (x equiv.), solvent (1 mL), T/°C, t/h, air, isolated yields, the ee values were determined by HPLC analysis.
1	Co(OAc)2·4H2O	0.5	2-BuOH	60	10	46	96
2	CoSO4·7H2O	0.5	2-BuOH	60	10	Trace	—
3	CoBr2	0.5	2-BuOH	60	10	18	95
4	Co(acac)2	0.5	2-BuOH	60	10	Trace	—
5	Co(OAc)2·4H2O	0.7	2-BuOH	60	10	43	96
6	Co(OAc)2·4H2O	0.3	2-BuOH	60	10	39	96
7	Co(OAc)2·4H2O	0.5	t-BuOH	60	10	45	96
8	Co(OAc)2·4H2O	0.5	n-BuOH	60	10	24	89
9	Co(OAc)2·4H2O	0.5	n-PrOH	60	10	17	93
10	Co(OAc)2·4H2O	0.5	EtOH	60	10	21	94
11	Co(OAc)2·4H2O	0.5	2-BuOH	80	10	46	94
12	Co(OAc)2·4H2O	0.5	2-BuOH	100	10	43	92
13	Co(OAc)2·4H2O	0.5	2-BuOH	60	20	63	96
14	Co(OAc)2·4H2O	0.5	2-BuOH	60	30	78	96
15	Co(OAc)2·4H2O	0.5	2-BuOH	60	36	89	96

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Reaction substrate scope

After establishing the optimal reaction conditions, we proceeded to evaluate the generality of this cobalt/Salox-catalyzed atroposelective synthesis of C–O axially chiral compounds. First, the substrate scope of benzamides was examined (Fig. 2). Substrates bearing diverse functionalities, including para-fluoro, chloro, bromo, iodo, methyl, tert-butyl, phenyl, methoxyl, trifluoromethoxy, and nitrile groups, reacted smoothly with phenylethynyl ether 1a, delivering the corresponding C–O axially chiral products (3b–3k) in good yields (69–95%) with excellent enantioselectivities (94–99% ee). The benzamides featuring para-sterically bulky anthracene or carbazole substituents were also able to give products 3l and 3m (54% yield, 65% ee, and 85% yield, 85% ee, respectively). Compound 3n was obtained as the sole product in 85% yield with 96% ee starting from meta-methyl substituted benzamide. The ortho-methyl substituted substrate reacted to deliver 3o in 35% yield with 95% ee. The substrates with extended aromatic systems, including either naphthalene or pyrene, were smoothly transformed into corresponding products 3p and 3q in 18% yield with 95% ee, and 71% yield with 94% ee, respectively.

Fig. 2 Scope of benzamides for the synthesis of C–O axially chiral aryl-isoquinolinol ethers. Reaction conditions: 1a (0.12 mmol), 2 (0.1 mmol), Co(OAc)₂·4H₂O (10 mol%), L8 (20 mol%), Mn(OAc)₂·4H₂O (0.5 equiv.), 2-BuOH (1 mL), 60 °C, 36 h, air, isolated yields, the ee values were determined by HPLC analysis. ^a48 h.

Subsequently, the compatibility of phenylethynyl ethers was investigated with benzamide 2a under the optimized conditions (Fig. 3). The alkynes bearing divergent substituted aryl on the phenolic motif, including para-halogen, alkyl, and aryl substituted phenyl substituents, were well tolerated, furnishing the corresponding C–O axially chiral compounds (3r–3v) in 85–96% yield with 94–97% ee values. The strong electron-withdrawing CF₃ group did not interfere with the reaction, giving 3w in 92% yield with 95% ee. The meta-alkyl substituted substrate also reacted well to afford 3x (80% yield, 96% ee). We then examined modifications on the gem-diaryl propargyl alcohol motif. The products (3y–3z, 3za–3zf) bearing para-halogen, electron-donating, electron-withdrawing groups and meta-chloro groups on the gem-diaryl motif were produced smoothly in 83–97% yields with 96–97% ee values. The absolute configuration of 3za was confirmed by X-ray crystallographic diffraction (Fig. 3, 3za, CCDC 2516693), and detailed analysis indicates a typical π–π interaction (typical π-stacking distances, face to face separations, 3.4–3.8 Å,⁸⁴ find details in the SI, Fig. S8) between the isoquinolinone ring and the phenyl substituent of arylether moiety. This weak interaction might play a key role in the stereocontrol of the transformation, meanwhile potentially contribute to the configurational stability of C–O axially chiral products. The fluorene and thiophene derived alkynes were also suitable, affording 3zg and 3zh in 55% yield with 85% ee, and 81% yield with 80% ee, respectively. To evaluate steric effects of the tertiary propargyl alcohol motif, we replaced gem-diaryl group with less hindered alternatives. Using a gem-dimethyl, cyclopentyl- and cyclohexyl-substituted substrates furnished corresponding products 3zi–3zk in 73–95% yields with moderate enantioselectivities (77–81% ee values). Compound 3zl was obtained in 90% yield with only 27% ee. The low enantioselectivity likely arises from the loss of π–π interaction upon replacement of the phenyl group by a methyl group, which would reduce the rotational barrier. The alkynes containing unsymmetrical tertiary alcohol motif was also examined, furnishing products 3zm (ΔG^‡ = 31.9 kcal mol⁻¹, Table S19 and Fig. S4–S5) in 87% yield (8 : 1 dr, 83% ee). Afterwards, we examined the scope of nonpropargyl substrates. Notably, the phenylethynyl ether bearing a TMS group in place of the tertiary alcohol motif provided both desired product 3zn (35%, 82% ee) and compound 3zn′ (21%, single diastereomer, 99% ee). The latter, with directing group still attached, possesses multiple chiral elements involving remote C–O and C–N axial chiralities.

Fig. 3 Scope of phenylethynyl ethers for the synthesis of C–O axially chiral aryl-isoquinolinol ethers. Reaction conditions: 1 (0.12 mmol), 2a (0.1 mmol), Co(OAc)₂·4H₂O (10 mol%), L8 (20 mol%), Mn(OAc)₂·4H₂O (0.5 equiv.), 2-BuOH (1 mL), 60 °C, 36 h, air, isolated yields, the ee values were determined by HPLC analysis. ^aThe dr value was determined by ¹H-NMR. ^bCompound 3zn′ was obtained as single diastereomer, DG = 2-(methylamino)pyridine.

In recent years, the enantioselective construction of molecules containing multiple axially chiral elements has garnered increasing attention from the synthetic community.^{9,61,69,72–77,85–99} However, the synthesis of such architectures featuring C–O axial chirality has not been achieved. Accordingly, we sought to explore the simultaneous installation of both C–O and C–N chiral axes under the aforementioned conditions.

Initially, the synthesis of compound 5a from phenylethynyl ether 1x and benzamide 4a bearing 8-aminoquinoline as directing group was set as a template to verify this concept. Gratifyingly, further optimization of this reaction (based on the previously established conditions, Table S11–S14 in SI) provided satisfactory results. Under the optimized conditions, the desired product 5a was obtained in 89% yield, 19 : 1 dr and 99% ee with Co(OAc)₂·4H₂O (10 mol%) as catalyst, L8 as ligand, Mn(OAc)₂·4H₂O/O₂ as the oxidant, NaOPiv·H₂O (1 equiv.) as the additive, in 2-BuOH (0.1 M) at 40 °C under air atmosphere. The absolute configuration of 5a was confirmed by X-ray crystallographic diffraction (Fig. 4, 5a, CCDC 2504636). The π–π interaction (find details in the SI, Fig. S9) between the isoquinolinone ring and the phenyl substiuent of phenolic moiety was also observed, which might be helpful for the stabilization of the configuration. Then the generality of this approach was scrutinized under the optimal conditions (Fig. 4). Benzamides substituted with para-halogen (including F, Cl, Br, I), or alkyl groups (Me, ^tBu) were all accommodated to give corresponding products (5b–5g) in 82–92% yield with 12:1–16 : 1 dr and 96–99% ee. Substrates with either electron-donating (OMe) or electron-withdrawing (OCF₃, CN, CF₃) groups at the para position were well tolerated, furnishing products 5h–5k in 90–96% yields with 13:1–17 : 1 dr and 99% ee. The meta-methyl-substituted benzamide provided 5l in 67% yield (16 : 1 dr, 99% ee). Compound 5m was obtained in 57% yield with 13 : 1 dr and 99% ee arising from 2-thiophenecarboxamide derivative. Afterwards, replacing the methyl with bulky isopropyl and tertiary butyl groups at 8-aminoquinoline furnished corresponding products 5n and 5o in good yields (84%, 93%, respectively) with 99% ee and moderate diastereoselectivity (9 : 1, 11 : 1 dr). Notably, the substrate with 5- bromo-substituted directing group afforded 5p in 74% yield with excellent diastereoselectivity (>20 : 1 dr, 99% ee). The compatibility of diverse phenylethynyl ethers was then evaluated. The alkynes bearing para-methyl, tert-butyl, phenyl, chloro, and CF₃ substituted phenyl groups on the phenolic motif were well tolerated to give products (5q–5u) in 82–93% yield with >20 : 1 dr and 99% ee. The naphthyl-containing alkynes gave 5v in 90% yield (>20 : 1 dr, 96% ee). The meta-methyl substituted substrate afforded 5w in 97% yield (15 : 1 dr, 99% ee). The substrate with para-^tBu in place of methyl at phenol moiety remained efficient, providing 5x in 92% yield (19 : 1 dr, 99% ee). Introducing a more bulky Ph₂MeSi group instead of TMS smoothly afforded 5y in 97% yield (>20 : 1 dr and 99% ee). Replacing the phenyl with methyl afforded 5z in 87% yield with 6 : 1 dr and 99% ee. We also examined modifications of phenylethynyl ether by installing tertiary alcohol motif in place of TMS group. The compounds 5za–5zc were successfully obtained in good yields (71–91%) with excellent stereocontrol (single diastereomer, 95–99% ee). Finally, replacing the TMS group with a benzoyl group provided compound 5zd in 82% yield with 14 : 1 dr and 99% ee.

Fig. 4 Substrate cope for the synthesis of C–O/C–N diaxially chiral compounds. Reaction conditions: 1 (0.12 mmol), 4 (0.1 mmol), Co(OAc)₂·4H₂O (10 mol%), L8 (20 mol%), Mn(OAc)₂·4H₂O (0.5 equiv.), NaOPiv·H₂O (1 equiv.), 2-BuOH (1 mL), 40 °C, 36 h, air, the dr values were determined by HPLC analysis. ^aThe dr value was determined by ¹H-NMR. ^bLigand L9 was used instead of L8.

Further transformations and synthetic applications

To demonstrate the synthetic utility of this protocol, gram-scale preparations of the representative C–O axially chiral compounds were carried out. Compound 3a was prepared in a reaction scale of 2.5 mmol, affording a good result without erosion on reaction efficacy and stereoselectivity (1.20 g, 83% yield, 96% ee) (Fig. 5a). Furthermore, a series of downstream transformations were performed on product 3a. The free N–H moiety of the isoquinolinone core could be readily functionalized: alkylations with methyl iodide, benzyl bromide, or propargyl bromide furnished products 6, 7, and 8 in good yields (86%, 85%, and 85%, respectively) without loss of enantiopurity. Additionally, treatment of 3a with PhNTf₂ and Cs₂CO₃ in THF at 60 °C provided the C–O axially chiral aryl-isoquinoline ether compound 9 in 92% yield with 96% ee. This intermediate served as a versatile precursor for further diversifications. For instance, a Pd(PPh₃)₄-catalyzed Suzuki–Miyaura cross-coupling reaction with 4-tolylboronic acid delivered compound 10 in 88% yield with 96% ee. Subsequent removal of OTf group under Pd(OAc)₂/dppf catalysis afforded compound 11 in 78% yield with 96% ee. Throughout all derivatizations, no erosion of enantiomeric purity was observed, underscoring the robustness of the chiral framework under diverse reaction conditions. The gram-scale synthesis of compound 5a maintained excellent stereoselectivity (19 : 1 dr, 99% ee), and only slight decreased yield (76%) was observed (Fig. 5b). Finally, desilylation of 5a with TBAF smoothly gave compound 12 in 99% yield with 3 : 1 dr and 99% ee. The results indicates that removal of TMS group decreases the rotational energy barrier of C–O axis, while with negligible effect on the stability of C–N axis. Furthermore, the experimental studies of racemization barriers (Fig. 5c) for compound 3a (recovery: 90%) afforded a ΔG^‡ (C–O) value of 33.5 kcal mol⁻¹, with a half-time (t_1/2) of 6.0 × 10³ years at 25 °C. The measurement of epimerization barriers for compound 5a (recovery: 91%, 100 °C; 89%, 120 °C) revealed a ΔG^‡ (C–O) value of 33.4 kcal mol⁻¹, and a ΔG^‡ (C–N) value of 33.7 kcal mol⁻¹. The half-times (t_1/2) were determined to be 4.9 × 10³ years for C–O axis and 8.8 × 10³ years for C–N axis at 25 °C, respectively. These detailed studies underscore the high stability of prepared C–O axially chiral scaffolds.

Fig. 5 Investigations of synthetic utilities. (a) Gram-scale synthesis and divergent transformations of compound 3a. (b) Gram-scale synthesis and transformation of compound 5a. (c) Determination of racemization barriers for 3a and epimerization barriers for 5a.

Afterwards, the ultraviolet-visible spectroscopy and fluorescence spectrum (Table S21–23) of representative C–O atropisomers were studied. The substitution patterns at either the benzamide or alkyne moieties had negligible effect on the maximum absorption wavelength in UV-vis of compounds 3 and 5. Among the C–O axially chiral products 3 and 5, introducing para-bromo (3d), iodo (3e), cyano (3k), and ortho-alkyl (3o) groups at the isoquinolinone moiety resulted in blue shift for the fluorescence spectrum, as well as compound 3zh with gem-dithiophene tertiary alcohol motif. Pronounced red shift was observed for compounds with para-phenyl (3h), carbazole (3m) group or extended aromatic fragments (3p, naphthalene, and 3q, pyrene, respectively). Compound 5a (446 nm) bearing diaxial architecture displayed a bathochromic shift compared with 3a (410 nm). Introducing para-^tBu (5g), methoxy (5h), and cyano (5j) led to evident red shift. The longest maximum emission wavelength (540 nm) was obained with compound 5v bearing a naphthyl group at the phenol moiety. In comparison, compound 5zd with a benzoyl group instead of TMS exhibits the shortest maximum emission wavelength (414 nm). Notably, a dual emission was observed for compounds 3h, 3p, 3q, and 5w at 375 nm and 444 nm, 370 nm and 445 nm, 388 nm and 518 nm, 394 nm and 502 nm, respectively (Fig. S10).

Mechanistic studies

To gain insights into this transformation, several deuterium-labeling experiments were conducted (Fig. 6). The H/D exchange experiments (Fig. 6a) were carried out with 2a or [D₅]-2a, as well as 4a or [D₅]-4a in the absence of alkynes, detecting measurable H/D exchangement. The outcomes demonstrate that the C–H cleavage step is reversible. Meanwhile, we performed the H/D exchange experiments of 2a with 1a under standard conditions for 6 h, and no deuteration was observed. These findings are consistent with a reversible C–H activation, with the subsequent alkyne insertion being considerably faster. Subsequently, two sets of parallel (Fig. 6b) kinetic isotope effects (KIE) studies at low conversions gave k_H/k_D values of 1.40 and 1.69, respectively. The results suggest that C–H bond activation is likely not involved in the rate-determining step. Moreover, the non-linear effect (NLE) studies for the traceless directing group approach revealed a linear relationship between the ee values of chiral Salox ligand and the C–O axially chiral product 3a. However, a positive NLE outcomes was obtained for the synthesis of C–O/C–N diaxially chiral compound 5a, which indicates that multiple chiral ligands perhaps participate in the coordination to form the cobalt species in the catalytic cycle.

Fig. 6 Mechanistic studies. (a) H/D exchange experiments. (b) Parallel KIE experiments. (c) Non-linear effect studies.

Based on the experimental results and literature reports,^53–55 we proposed a plausible mechanism as shown in Fig. 7. In the presence of chiral ligand L8, the Co(II) is oxidized by O₂/Mn(OAc)₂·4H₂O to form active Co(III) species Int-1. In the case with 7-methyl-8-aminoquinoline as the directing group, a positive NLE result indicates that two ligands might coordinates with Co to form complex [Co-L₂]_n species Int-1′.¹⁰⁰ The Int-1 or Int-1′ undergoes coordination with benzamides 2a or 4a bearing different directing groups, and C–H activation to afford Int-2 and Int-2′, respectively. The following ligand exchange and migration insertion of Int-2 with alkyne 1a delivers a seven-membered alkenyl cobaltacycle intermediate Int-3. The subsequent reductive elimination provides a Co(I) species Int-4, which is likely to be stabilized by two non-covalent π–π interactions. The first interaction arises between the phenyl moiety of the oxazoline scaffold and the pyridyl unit of the directing group. The second one is established between the isoquinolinone ring and the phenyl substituent of the phenylethynyl ether. The latter is corroborated by X-ray crystallographic diffraction data for compounds 3za and 5a (Find details in Table S8–S9 in SI). Collectively, these two π–π stacking interactions are postulated to play a pivotal role in stabilizing the cobalt species and the axial chirality configuration of the products. The Int-4 is transformed to Co(III) Int-5 via an oxidative addition of Co(I) to N–N bond.^80–83,101 Finally, protodemetallation and ligand exchange of Int-5 affords the desired C–O axially chiral aryl-isoquinolinone ether 3a, and simultaneously releases the Co(III) catalyst and L8. In the case of benzamide 4a bearing 7-methyl-8-aminoquinoline as the directing group, the corresponding intermediate Int-2′ undergoes migration insertion with alkyne 1x to give Int-6. After the subsequent reductive elimination, the final C–O/C–N diaxially chiral product 5a was produced. The regenerated Co(I) could be further oxidized to active Co(III) species.

Fig. 7 Proposed mechanism.

Conclusions

In conclusion, we have developed an atroposelective construction of a new type of C–O axially chiral aryl-heterocyclic ethers through Co/Salox catalyzed asymmetric C–H activation/annulation of benzamides with phenylethynyl ethers. This strategy features a de novo synthetic approach, enabling simultaneous establishments of heteroaromatic ring and C–O chiral axis. A broad range of C–O axially chiral aryl-isoquinolinol ethers were efficiently synthesized with excellent stereoselectivity. Notably, the achievement of in situ removal of N,N-bidentate directing group secured the traceless directing approach. Moreover, an array of structurally diverse C–O axially chiral products bearing multiple chiral axes were afforded in good yields, accompanied by excellent enantio- and diastereoselectivity. High rotational energy barriers and configurational stability of the synthesized C–O atropisomers were identified through experimental studies. Furthermore, mechanistic investigations were conducted for gaining deep insights into this protocol. The synthetic utility was demonstrated through gram-scale synthesis and divergent transformations. This work provides a new synthetic paradigm for constructing C–O axially chiral architectures, and illuminates a promising perspective in the field of transition-metal-catalyzed C–H activation for the atroposelective construction of novel axial chirality.

Author contributions

Y. D., D. Y., and J.-L. N. conceived the concept and prepared the manuscript. Y. Z., Y. X., and B. G. conducted the experiments and analyzed the data. Y. Z. and Y. X. contributed equally to this work. All the authors participated in the discussions of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

CCDC 2516693 (for 3za) and 2504636 (for 5a) contain the supplementary crystallographic data for this paper.^102a,b

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: experimental procedures, optimization studies, mechanistic studies, and characterization data of new compounds. See DOI: https://doi.org/10.1039/d6sc02299e.

Acknowledgements

This work was supported by the Natural Science Foundation of Henan Province (242300421033, 252300421178, 232301420007, 242301420059), and National Natural Science Foundation of China (22271260, 22401266).

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Footnote

† These authors contributed equally to this work.

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