A Chiral Relay Race: Stereoselective Synthesis of Axially Chiral Biaryl Diketones through Ring-Opening of Optical Dihydrophenan-threne-9,10-diols

Abstract

We report herein a point-to-axial chirality transfer reaction of optical dihydrophenanthrene-9,10-diols for the synthesis of axially chiral diketones. Two sets of conditions, namely a basic tBuOK/air atmosphere and an acidic NaClO/n-Bu₄NHSO₄, were developed to oxidatively cleave the C-C bond, resulting in the formation of axially chiral biaryl diketones. Finally, brief synthetic applications of the obtained chiral aryl diketones were demonstrated.

1. Introduction

Atropisomerism is a type of conformational chirality, which occurs when the free rotation around a single bond is inhibited mostly due to steric hinderance or electronic constraints adjacent to the single bond. As a result, two conformers are stable enough without interconversion; thereby, both of the chiral enantiomers can be isolated and investigated at a proper temperature. This phenomenon can be found in bioactive natural products and drugs [1,2,3,4,5,6,7,8], which have wide applications in asymmetric catalysis and material science.

Axially chiral biaryl compounds is an important type of atropisomers, which has been widely applied in the fields of organic synthesis and chiral material science [9,10,11,12,13,14,15]. The catalytic asymmetric synthesis of axially chiral biaryls has become an area of significant interests in recent years [16,17,18,19,20,21,22,23,24,25,26]. Biaryl atropisomers can be categorized into two structural types, namely bridged and non-bridged. The stability of the chirality of these compounds is significantly impacted by the size of the bridged ring and the chemical nature of its substituents. In general, the ortho,ortho’-fused five- or six-membered ring tends to induce the interconversion of two enantiomers of atropisomers by lowering the rotational barrier. In the 1990s, Bringmann and his colleagues pioneered the stereoselective ring-opening of biaryl lactones through either a chiral pool strategy or an asymmetric catalysis method based on the dynamic properties of the lactones’ conformers (Scheme 1a) [27]. Subsequent efforts by research groups of Hayashi, Gu, and others have led to the catalytic asymmetric ring-opening of a diverse range of heterocyclic compounds, encompassing S-, O-, I+-, and Si-containing compounds [28,29,30,31,32]. In 2019, Gu and co-workers successfully achieved catalytic asymmetric cleavage of C-C bonds by utilizing palladium-involved β-carbon elimination [33].

In 2022, we observed that optically active 8H-indeno [1,2-c]thiophen-8-ols would undergo a stereoselective ring-opening reaction with an achiral palladium complex, resulting in the formation of axially chiral biaryls (Scheme 1b) [34,35]. This chirality relay is based on the fact that one of the aryl rings would approach the Pd atom, ultimately resulting in the construction of axial chirality. In contrast to the 8H-indeno [1,2-c]thiophen-8-ols, the stereogenic carbon center of α-hydroxy ketone induces the configuration of the biaryl structure (Scheme 1c) [36,37]. For example, when the R-configuration carbon center is involved, the biaryl skeleton favors the S_a configuration, which then leads to the construction of S-axially chiral carboxylic acids and nitriles from the corresponding α-hydroxy ketone and oxime ester, respectively. In this work, we report an oxidative chirality relay ring-opening reaction of dihydrophenanthrene-9,10-diols for the synthesis of axially chiral diketones (Scheme 1d).

2. Results and Discussion

In previous work, we developed an efficient asymmetric arylation reaction of phenanthrene-9,10-diones for the preparation of optically active α-hydroxyl phenanthrenones [36]. Diol 2a was obtained with ease in 95% enantiomeric excess (ee) by the arylation of phenylmagnesium bromide in THF, exhibiting complete diastereoselectivity. The single crystal structure of 2a revealed a notable distortion of the biaryl skeleton (Appendix A). Treatment of 2a with 3.0 equivalents of tBuOK at room temperature under an oxygen atmosphere delivered axially chiral biaryl diketone 3a in 95% yield; however, a slight decrease in enantiomeric excess was observed (Table 1, entry 1). Lowering the reaction temperature to 0 °C enhanced the efficiency of chirality transfer, but the yield of 3a dropped from 95% to 85%. Notably, the ee of 3a reached 95% at 30 °C under an air atmosphere, which was possible due to the decreased reaction rate (entry 3). The use of 3.0 equivalents of tBuOK was found to be crucial. With 2.0 equivalents of tBuOK, the yield dropped significantly, while no diketone was observed with only 1.0 equivalent of tBuOK (entries 4–5). Notably, potassium hydroxide and potassium carbonate failed to induce the oxidative C-C bond cleavage ring-opening reaction (entries 6–7).

After determining the optimal conditions, we proceeded to test the substrate scope of this ring-opening reaction (Scheme 2). It was found that S_T (defined as the ee value of the product divided by the ee value of the starting material, S_T = ee₃/ee₁ × 100%) remained consistently high (96–100%), regardless of the electronic effect of the para- or meta- substituents, such as halogen atom, alkyl, methoxy, thiomethyl, trifluoromethoxy, and vinyl groups (3b–3o). However, the yields of diketones slightly decreased when the aryl group contained para or meta halides (3c–e, 3j, and 3k). High-yield and enantioselective ring-opening products can also be obtained when substrates bear multiple substituted phenyl groups (3p, 3r and 3s). The chiral binaphthyl atropisomer can also be obtained with high yield and selectivity through this oxidative chirality relay strategy (3w). The Grignard reagent involved an arylation reaction, which also enabled us to synthesize unsymmetrical diaryl diols, which were also suitable for a tBuOK-induced ring-opening reaction to yield diketones in stereoselectivity (3t–3u). Additionally, introducing β,β′-dimethyl groups did not negatively affect this base-promoted chirality transfer ring-opening reaction (3v). Notably, the ortho,ortho’-dimethoxy-, or tertiary alcohol with an alkyl-, alkenyl-, or cyclopropyl-substituent were unreactive in the presence of tBuOK under an air atmosphere. However, the ring-opening reaction with sodium hypochlorite under n-Bu₄NHSO₄ buffer proceeded smoothly to give the diketones in moderate to excellent yields (3x–3aa). The absolute configuration of 3x was confirmed by single crystal X-ray diffraction analysis (Appendix A).

It was found that 2x remained inert in the presence of tBuOK under an air atmosphere. In order to eliminate the possibility of the electronic effect caused by the two methoxy groups, diol 2bb was synthesized, and it also exhibited poor reactivity under the identical conditions (Scheme 3). This suggests that, in fact, the torsional strain of diol may actually be conducive to its C-C bond cleavage.

It was hypothesized that diol 2a would undergo deprotonation, followed by oxidation with oxygen to form the radical Int2 (Scheme 4a). Subsequently, the β-scission of Int2 would produce a biaryl carbon radical Int3, eventually leading to the formation of diketone 3a through a second oxidation by either O₂ or anion radical O₂⁻·. In our previous studies, the possible radical intermediate was trapped by DMPO and analyzed by electron paramagnetic resonance (EPR) [36]. In this work, a TEMPO adduct was detected by high resolution mass spectra (ESI). Alternatively, under acidic conditions, 2y could react with NaClO to form tertiary alkyl hypochlorite Int4 or Int4′ (or both), which would then undergo elimination to cleave the C-C bond and yield 3y (Scheme 4b).

The utilities of the obtained axially chiral compounds were briefly investigated. In a gram-scale (3.0 mmol of 1a) reaction, 3a was successfully obtained with high-yield and complete chirality relay (Scheme 5a). The diketone group in 3a could be easily converted to the corresponding olefin 4 under a standard Wittig olefination condition, yielding an 86% yield and 93% ee (Scheme 5b). The oxidation of the two methyl groups was achieved by treating with N-bromosuccinimide followed by AgNO_3, resulting in the formation of dialdehyde 5 with an overall yield of 68% and 93% ee. The arylation of 2a with PhLi afforded BAMOL (1,1′-biaryl-2,2′-dimethanol) derivative 6 in a 71% yield with 93% ee. The diol has exhibited excellent performance as a hydrogen bonding catalyst in the hetero-Diels–Alder reaction [38].

3. Materials and Methods

3.1. General Information

Nuclear magnetic resonances were recorded on Bruker−400 MHz or Bruker−500 MHz instruments. Reference values for residual solvents were taken as δ = 0.00 ppm (TMS), δ = 7.26 ppm (CDCl₃) for ¹H NMR; δ = 77.00 ppm (CDCl₃) for ¹³C NMR. High-resolution mass spectral analysis (HRMS) was performed on Waters XEVO G2 Q−TOF. For the copies of spectroscopies, please see Supplementary Materials.

All reactions were performed under an inert atmosphere of dry nitrogen, unless otherwise stated. Toluene was distilled over calcium hydride under an atmosphere of nitrogen. Tetrahydrofuran was distilled over sodium in the presence of benzophenone under an atmosphere of nitrogen. All the optical alcohols were known compounds and were prepared according to the procedure developed in our laboratory [36,37].

3.1.1. General Procedure for the Synthesis of Target Compounds 3a–3w

Under a nitrogen atmosphere, R’-MgBr (1.0 M, 0.60 mL, 0.60 mmol, 3.0 equiv) was added dropwisely to a solution of 1a–1w (0.20 mmol, 1.0 equiv) in anhydrous THF (3.0 mL) at 0 °C. After being stirred at 25 °C for 4 h, the reaction was quenched with water (15 mL) and extracted with EtOAc (10 mL × 3). The combined organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated to afford the crude diol, which was used in next step without further purification.

Under an air atmosphere to a mixture of the above crude diol in anhydrous THF (5.0 mL), t-BuOK (67.3 mg, 0.60 mmol, 3.0 equiv) was added at room temperature and stirred for 30 min. The solvent was removed, and the residue was purified by flash chromatography on silica gel (PE/EtOAc) to afford 3a–3w.

The reaction of 1a (62.8 mg, 0.20 mmol, 95% ee, 1.0 equiv) afforded product 3a (73.9 mg, 95%, 95% ee, S_T = 100%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ − 3.10 (c 1.50, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 5:95, flow: 0.8 mL/min, λ = 254 nm, t_R = 6.9 min (minor), 8.3 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.46–7.43 (m, 4H), 7.43–7.40 (m, 2H), 7.29–7.25 (m, 2H), 7.25–7.22 (m, 2H), 7.16–7.12 (m, 2H), 7.09–7.04 (m, 4H). 2.16 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 197.1, 139.0, 138.6, 137.2, 136.9, 132.3, 131.8, 130.2, 127.6, 126.8, 126.1, 20.2. HRMS (ESI) calcd for C₂₈H₂₃O₂ [M + H]⁺ 391.1693, found 391.1696.

The reaction of 1b (70.0 mg, 0.20 mmol, 93% ee, 1.0 equiv) afforded product 3b (74.2 mg, 88%, 92% ee, S_T = 99%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 47.4 (c 1.60, CH₂Cl₂). HPLC conditions: Chiralcel IC-3, isopropanol/hexane = 3:97, flow: 0.8 mL/min, λ = 254 nm, t_R = 15.7 min (major), 18.4 min (minor). ¹H NMR (500 MHz, CDCl₃) δ 7.45–7.39 (m, 2H), 7.33–7.28 (m, 4H), 7.27–7.22 (m, 2H), 7.12 (dd, J = 7.5, 1.5 Hz, 2H), 6.83 (d, J = 8.0 Hz, 4H), 2.24 (s, 6H), 2.17 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 196.7, 143.0, 139.1, 138.3, 137.1, 134.5, 131.5, 130.5, 128.2, 126.3, 126.1, 21.4, 20.2. HRMS (ESI) calcd for C₃₀H₂₆O₂Na [M+Na]⁺ 441.1825, found 441.4823.

The reaction of 1c (66.4 mg, 0.20 mmol, 92% ee, 1.0 equiv) afforded product 3c (70.8 mg, 83%, 88% ee, S_T = 96%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ − 104 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 2:98, flow: 0.8 mL/min, λ = 254 nm, t_R = 10.6 min (minor), 19.3 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.48–7.46 (m, 2H), 7.46–7.42 (m, 4H), 7.31–7.22 (m, 2H), 7.12 (dd, J = 8.0, 1.0 Hz, 2H), 6.81–6.72 (m, 4H), 2.15 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 195.4, 166.4 (d, J = 255.4 Hz), 139.2, 138.4, 136.6, 133.5 (d, J = 3.0 Hz), 132.9 (d, J = 9.3 Hz), 132.0, 126.4, 126.3, 114.8 (d, J = 21.8 Hz), 20.2. ¹⁹F NMR (471 MHz, CDCl₃) δ −105.8. HRMS (ESI) calcd for C₂₈H₂₁F₂O₂ [M + H]⁺ 427.1504, found 427.1510.

The reaction of 1d (69.6 mg, 0.20 mmol, 93% ee, 1.0 equiv) afforded product 3d (75.3 mg, 82%, 89% ee, S_T = 96%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 55.0 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 3:97, flow: 0.8 mL/min, λ = 254 nm, t_R = 8.8 min (minor), 12.0 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.44 (d, J = 7.5 Hz, 2H), 7.38–7.36 (m, 2H), 7.36–7.33 (m, 2H), 7.30–7.24 (m, 2H), 7.14–7.09 (m, 2H), 7.10–7.02 (m, 4H), 2.15 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 195.7, 139.32, 139.26, 138.3, 136.4, 135.3, 132.0, 131.6, 128.0, 126.4, 126.3, 20.1. HRMS (ESI) calcd for C₂₈H₂₁Cl₂O₂ [M + H]⁺ 459.0913, found 459.0915.

The reaction of 1e (78.4 mg, 0.20 mmol, 95% ee, 1.0 equiv) afforded product 3e (87.7 mg, 80%, 92% ee, S_T = 97%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ − 2.87 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 2:98, flow: 0.8 mL/min, λ = 254 nm, t_R = 8.8 min (minor), 11.1 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.49–7.47 (m, 2H), 7.47–7.46 (m, 2H), 7.45–7.43 (m, 2H), 7.32–7.29 (m, 2H), 7.29–7.27 (m, 2H), 7.17 (dd, J = 7.5, 1.5 Hz, 2H), 7.12–7.07 (m, 4H), 2.19 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 197.1, 139.0, 138.6, 137.3, 136.9, 132.3, 131.8, 130.3, 127.6, 126.8, 126.2, 20.2. HRMS (ESI) calcd for C₂₈H₂₀Br₂O₂Na [M+Na]⁺ 568.9722, found 568.9731.

The reaction of 1f (68.8 mg, 0.20 mmol, 89% ee, 1.0 equiv) afforded product 3f (77.4 mg, 86%, 88% ee, S_T = 99%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 184 (c 1.40, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 3:97, flow: 0.8 mL/min, λ = 254 nm, t_R = 17.0 min (minor), 24.2 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.41 (d, J = 7.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 4H), 7.26–7.21 (m 2H), 7.13–7.03 (m, 2H), 6.54–6.38 (m, 4H), 3.70 (s, 6H), 2.18 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 195.7, 162.8, 139.3, 138.1, 137.2, 132.6, 131.3, 129.9, 126.1, 125.9, 112.7, 55.0, 20.2. HRMS (ESI) calcd for C₃₀H₂₆O₄Na [M+Na]⁺ 473.1723, found 473.1722.

The reaction of 1g (79.6 mg, 0.20 mmol, 97% ee, 1.0 equiv) afforded product 3g (80.5 mg, 72%, 95% ee, S_T = 98%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 8.75 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 2:98, flow: 0.8 mL/min, λ = 254 nm, t_R = 8.5 min (minor), 10.2 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.53–7.49 (m, 4H), 7.46 (d, J = 7.5 Hz, 2H), 7.31–7.26 (m, 2H), 7.14 (dd, J = 8.0, 1.5 Hz, 2H), 6.94 (d, J = 8.5 Hz, 4H), 2.16 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 195.4, 152.2, 139.2, 138.5, 136.4, 135.3, 132.3, 132.2, 126.6, 126.4, 120.1 (q, J = 259 Hz), 119.2, 20.1. ¹⁹F NMR (471 MHz, CDCl₃) δ -57.80. HRMS (ESI) calcd for C₃₀H₂₁F₆O₄ [M + H]⁺ 559.1339, found 559.1348.

The reaction of 1h (65.6 mg, 0.20 mmol, 95% ee, 1.0 equiv) afforded product 3h (72.1 mg, 86%, 94% ee, S_T = 99%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 40.5 (c 1.40, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 2:98, flow: 0.8 mL/min, λ = 254 nm, t_R = 7.6 min (minor), 8.7 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.43 (d, J = 7.5 Hz, 2H), 7.31–7.27 (m, 2H), 7.27–7.23 (m, 2H), 7.14–7.09 (m, 4H), 7.07 (d, J = 7.5 Hz, 2H), 7.00–6.96 (m, 2H), 2.19 (s, 6H), 2.04 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 197.3, 139.2, 138.5, 137.4, 137.2, 137.0, 133.1, 131.7, 131.0, 127.6, 127.2, 126.6, 126.2, 21.0, 20.1. HRMS (ESI) calcd for C₃₀H₂₆O₂Na [M+Na]⁺ 441.1825, found 441.1828.

The reaction of 1i (71.2 mg, 0.20 mmol, 94% ee, 1.0 equiv) afforded product 3i (87.8 mg, 92%, 92% ee, S_T = 98%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ − 5.75 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 2:98, flow: 0.8 mL/min, λ = 254 nm, t_R = 7.6 min (minor), 8.7 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.46–7.42 (m, 2H), 7.41–7.37 (m, 2H), 7.28–7.23 (m, 2H), 7.21–7.19 (m, 2H), 7.18–7.16 (m, 2H), 7.16–7.13 (m, 2H), 7.01–6.95 (m, 2H), 2.70 (p, J = 6.9 Hz, 2H), 2.19 (s, 6H), 1.09 (d, J = 4.0 Hz, 6H), 1.07 (d, J = 4.0 Hz, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 197.5, 148.3, 139.0, 138.8, 137.5, 137.1, 131.8, 130.5, 128.2, 128.1, 127.5, 127.0, 126.1, 33.6, 23.7, 23.5, 20.1. HRMS (ESI) calcd for C₃₄H₃₅O₂ [M + H]⁺ 475.2632, found 475.2640.

The reaction of 1j (66.4 mg, 0.20 mmol, 94% ee, 1.0 equiv) afforded product 3j (66.5 mg, 78%, 94% ee, S_T = 100%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 6.45 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 3:97, flow: 0.8 mL/min, λ = 254 nm, t_R = 8.1 min (minor), 11.3 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.45 (d, J = 7.5 Hz, 2H), 7.31–7.26 (m, 2H), 7.25–7.21 (m, 2H), 7.21–7.17 (m, 2H), 7.17–7.14 (m, 2H), 7.12–7.05 (m, 2H), 7.04–6.99 (m, 2H), 2.15 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 195.5 (d, J = 2.1 Hz), 162.1 (d, J = 248 Hz), 139.3 (d, J = 6.3 Hz), 139.1, 138.4, 136.4, 132.2, 129.3 (d, J = 7.4 Hz), 126.6, 126.4, 126.21, 126.18, 119.5 (d, J = 21.5 Hz), 116.6 (d, J = 22.3 Hz), 20.1. ¹⁹F NMR (471 MHz, CDCl₃) δ −112.5. HRMS (ESI) calcd for C₂₈H₂₁F₂O₂ [M + H]⁺ 427.1504, found 427.1510.

The reaction of 1k (69.6 mg, 0.20 mmol, 96% ee, 1.0 equiv) afforded product 3k (68.9 mg, 75%, 96% ee, S_T = 100%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 40.8 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 3:97, flow: 0.8 mL/min, λ = 254 nm, t_R = 9.4 min (minor), 13.8 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.45 (d, J = 7.5 Hz, 2H), 7.41–7.38 (m, 2H), 7.36–7.32 (m, 2H), 7.31–7.28 (m, 2H), 7.28–7.25 (m, 2H), 7.17–7.10 (m, 2H), 7.09–7.03 (m, 2H), 2.15 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 195.5, 139.2, 138.7, 138.4, 136.3, 134.2, 132.5, 132.3, 130.0, 129.1, 128.3, 126.54, 126.50, 77.2, 20.1. HRMS (ESI) calcd for C₂₈H₂₁Cl₂O₂ [M + H]⁺ 459.0913, found 459.0915.

The reaction of 1l (68.8 mg, 0.20 mmol, 95% ee, 1.0 equiv) afforded product 3l (86.5 mg, 96%, 91% ee, S_T = 96%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 27.6 (c 1.60, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 10:90, flow: 0.8 mL/min, λ = 254 nm, t_R = 7.7 min (minor), 8.5 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.44 (d, J = 7.5 Hz, 2H), 7.28–7.24 (m, 2H), 7.16 (dd, J = 8.0, 1.5 Hz, 2H), 7.00–6.97 (m, 4H), 6.97–6.93 (m, 2H), 6.85–6.80 (m, 2H), 3.63 (s, 6H), 2.18 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 196.8, 158.9, 139.1, 138.48, 138.47, 136.9, 131.8, 128.6, 126.6, 126.2, 123.2, 119.4, 113.7, 55.0, 20.1. HRMS (ESI) calcd for C₃₀H₂₇O₄ [M + H]⁺ 454.1904, found 451.1903.

The reaction of 1m (72.0 mg, 0.20 mmol, 83% ee, 1.0 equiv) afforded product 3m (71.4 mg, 74%, 83% ee, S_T = 100%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 20.0 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 3:97, flow: 0.8 mL/min, λ = 254 nm, t_R = 10.5 min (minor), 12.0 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.44 (d, J = 7.5 Hz, 2H), 7.30–7.27 (m, 2H), 7.27–7.24 (m, 2H), 7.18–7.15 (m, 2H), 7.15–7.14 (m, 2H), 7.14–7.10 (m, 2H), 7.01–6.91 (m, 2H), 2.32 (s, 6H), 2.17 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 196.7, 139.1, 138.8, 138.5, 137.8, 136.7, 132.0, 130.2, 127.9, 126.9, 126.8, 126.7, 126.3, 20.1, 15.2. HRMS (ESI) calcd for C₃₀H₂₇S₂O₄ [M + H]⁺ 483.1447, found 483.1453.

The reaction of 1n (78.0 mg, 0.20 mmol, 94% ee, 1.0 equiv) afforded product 3n (99.7 mg, 92%, 93% ee, S_T = 99%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 62.8 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 3:97, flow: 0.8 mL/min, λ = 254 nm, t_R = 9.9 min (minor), 11.9 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.66–7.61 (m, 2H), 7.48–7.40 (m, 6H), 7.32–7.28 (m, 2H), 7.28–7.27 (m, 2H), 7.27–7.26 (d, J = 3.0 Hz, 2H), 7.26–7.25 (m, 2H), 7.25–7.24 (m, 2H), 7.24–7.21 (m, 2H), 7.21–7.16 (m, 2H), 7.10–7.04 (m, 2H), 2.21 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 197.1, 140.5, 139.6, 139.2, 138.7, 137.7, 136.8, 132.0, 130.9, 128.91, 128.90, 128.6, 128.2, 127.4, 126.9, 126.8, 126.3, 20.2. HRMS (ESI) calcd for C₄₀H₃₁O₂ [M + H]⁺ 543.2319, found 543.2318.

The reaction of 1o (68.1 mg, 0.20 mmol, 92% ee, 1.0 equiv) afforded product 3o (73.5 mg, 83%, 90% ee, S_T = 98%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 24.6 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 2:98, flow: 0.8 mL/min, λ = 254 nm, t_R = 8.0 min (minor), 9.3 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.44 (d, J = 7.5 Hz, 2H), 7.42–7.39 (m, 2H), 7.31–7.29 (m, 2H), 7.28–7.27 (m, 2H), 7.27–7.22 (m, 2H), 7.16–7.10 (m, 2H), 7.03–6.97 (m, 2H), 6.52–6.35 (m, 2H), 5.55 (d, J = 17.5 Hz, 2H), 5.15 (d, J = 11.0 Hz, 2H), 2.18 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 197.0, 139.1, 138.5, 137.4, 137.2, 136.9, 135.8, 131.9, 130.0, 129.6, 127.94, 127.87, 126.6, 126.3, 114.7, 20.1. HRMS (ESI) calcd for C₃₂H₂₇O₂ [M + H]⁺ 443.2006, found 443.2011.

The reaction of 1p (68.4 mg, 0.20 mmol, 94% ee, 1.0 equiv) afforded product 3p (67.9 mg, 76%, 93% ee, S_T = 99%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 80.2 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel IC-3, isopropanol/hexane = 1:99, flow: 0.8 mL/min, λ = 254 nm, t_R = 13.0 min (major), 16.4 min (minor). ¹H NMR (500 MHz, CDCl₃) δ 7.42 (d, J = 7.5 Hz, 2H), 7.26–7.21 (m, 2H), 7.10–7.04 (m, 2H), 6.95 (s, 4H), 6.87 (s, 2H), 2.19 (s, 6H), 2.01 (s, 12H). ¹³C NMR (126 MHz, CDCl₃) δ 197.5, 139.3, 138.4, 137.3, 137.2, 133.9, 131.5, 128.1, 126.4, 126.2, 20.8, 20.1. HRMS (ESI) calcd for C₃₂H₃₁O₂ [M + H]⁺ 447.2319, found 447.2325.

The reaction of 1q (72.8 mg, 0.20 mmol, 94% ee, 1.0 equiv) afforded product 3q (91.2 mg, 93%, 94% ee, S_T = 100%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 282 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 2:98, flow: 0.8 mL/min, λ = 254 nm, t_R = 12.9 min (minor), 15.8 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.58 (dd, J = 8.5, 1.5 Hz, 2H), 7.54–7.51 (m, 2H), 7.51–7.47 (m, 2H), 7.32–7.30 (m, 2H), 7.30–7.28 (m, 2H), 7.28–7.27 (m, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.20–7.18 (m, 2H), 7.18–7.14 (m, 2H), 7.12–7.07 (m, 2H), 2.27 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 197.1, 139.5, 138.4, 137.0, 134.7, 133.9, 133.4, 131.7, 131.3, 129.2, 127.8, 127.7, 126.9, 126.4, 126.3, 125.7, 124.4, 20.2. HRMS (ESI) calcd for C₃₆H₂₇O₂ [M + H]⁺ 491.2006, found 491.2006.

The reaction of 1r (71.6 mg, 0.20 mmol, 90% ee, 1.0 equiv) afforded product 3r (86.1 mg, 90%, 90% ee, S_T = 100%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 63.2 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 3:97, flow: 0.8 mL/min, λ = 254 nm, t_R = 33.7 min (minor), 38.5 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.46–7.39 (m, 2H), 7.30–7.27 (m, 2H), 7.15–7.10 (m, 2H), 7.00–6.96 (m, 2H), 6.96–6.92 (m, 2H), 6.45 (d, J = 8.0 Hz, 2H), 5.96 (d, J = 1.5 Hz, 2H), 5.93 (d, J = 1.0 Hz, 2H), 2.17 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 195.1, 151.2, 147.2, 139.3, 138.1, 136.9, 131.8, 131.4, 127.7, 126.2, 125.9, 109.5, 107.0, 101.6, 20.2. HRMS (ESI) calcd for C₃₀H₂₃O₆ [M + H]⁺ 479.1489, found 479.1497.

The reaction of 1s (80.9 mg, 0.20 mmol, 92% ee, 1.0 equiv) afforded product 3s (91.3 mg, 80%, 90% ee, S_T = 98%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 238 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 2:98, flow: 0.8 mL/min, λ = 254 nm, t_R = 16.7 min (minor), 23.4 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.64 (s, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 7.5 Hz, 2H), 7.43 (d, J = 7.5 Hz, 2H), 7.34–7.28 (m, 2H), 7.22–7.18 (m, 4H), 7.16 (d, J = 7.5 Hz, 2H), 7.09–7.02 (m, 2H), 6.85 (d, J = 7.5 Hz, 2H), 2.28 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 196.3, 158.0, 156.1, 139.7, 138.2, 137.0, 131.9, 131.6, 129.0, 127.3, 126.5, 125.9, 124.0, 123.3, 122.8, 122.7, 120.6, 111.2, 110.7, 77.2, 20.3. HRMS (ESI) calcd for C₄₀H₂₇O₄ [M + H]⁺ 571.1904, found 571.1908.

The reaction of 1a (62.8 mg, 0.20 mmol, 95% ee, 1.0 equiv) with 3-MeOC₆H₄MgBr (0.60 mmol, 3.0 equiv) afforded product 3t (77.8 mg, 93%, 94% ee, S_T = 99%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 15.6 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 3:97, flow: 0.8 mL/min, λ = 254 nm, t_R = 9.0 min (minor), 10.8 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.45–7.43 (m, 2H), 7.42–7.39 (m, 2H), 7.31–7.27 (m, 1H), 7.27–7.23 (m, 2H), 7.17–7.11 (m, 2H), 7.11–7.05 (m, 2H), 7.03–6.97 (m, 2H), 6.96–6.91 (m 1H), 6.84–6.78 (m, 1H), 3.61 (s, 3H), 2.17 (s, 3H), 2.16 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 197.0, 196.8, 158.9, 139.0, 138.9, 138.6, 138.46, 138.45, 137.3, 136.9, 136.8, 132.2, 131.9, 131.7, 130.1, 128.6, 127.6, 126.9, 126.5, 126.2, 126.1, 123.3, 119.6, 113.6, 55.0, 20.14, 20.12. HRMS (ESI) calcd for C₂₉H₂₅O₃ [M + H]⁺ 421.1798, found 421.1807.

The reaction of 1a (62.8 mg, 0.20 mmol, 95% ee, 1.0 equiv) with 2-MeOC₆H₄MgBr (0.60 mmol, 3.0 equiv) afforded product 3u (65.4 mg, 78%, 94% ee, S_T = 99%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 2.10 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 3:97, flow: 0.8 mL/min, λ = 254 nm, t_R = 9.6 min (minor), 16.0 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.66–7.56 (m, 2H), 7.43–7.38 (m, 2H), 7.38–7.33 (m, 1H), 7.29–7.25 (m, 1H), 7.25–7.23 (m, 1H), 7.23–7.19 (m, 2H), 7.19–7.17 (m, 2H), 7.17–7.11 (m, 2H), 6.76–6.69 (m, 1H), 6.66–6.60 (m, 1H), 3.27 (s, 3H), 2.16 (s, 3H), 2.12 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 197.4, 196.6, 157.8, 139.4, 138.7, 138.5, 138.2, 137.8, 137.2, 132.4, 132.3, 132.1, 131.9, 131.2, 130.4, 128.6, 127.9, 127.6, 127.0, 126.4, 125.8, 119.7, 110.7, 54.6, 20.1, 20.0. HRMS (ESI) calcd for C₂₉H₂₄O₃Na [M + Na]⁺ 443.1618, found 443.1620.

The reaction of 1v (68.4 mg, 0.20 mmol, 95% ee, 1.0 equiv) afforded product 3v (80.0 mg, 95%, 93% ee, S_T = 98%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 13.5 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 3:97, flow: 0.8 mL/min, λ = 254 nm, t_R = 6.2 min (major), 7.6 min (minor). ¹H NMR (500 MHz, CDCl₃) δ 7.47–7.43 (m, 4H), 7.31–7.26 (m, 2H), 7.25–7.23 (m, 2H), 7.10–7.03 (m, 4H), 6.96–6.91 (m, 2H), 2.32 (s, 6H), 2.15 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 197.3, 138.9, 137.3, 137.1, 135.7, 135.5, 132.7, 132.2, 130.2, 127.5, 127.2, 21.0, 20.1. HRMS (ESI) calcd for C₃₀H₂₇O₂ [M + H]⁺ 419.2006, found 419.2012.

The reaction of 1w (68.4 mg, 0.20 mmol, 93% ee, 1.0 equiv) afforded product 3w (76.8 mg, 83%, 93% ee, S_T = 100%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 46.5 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 5:95, flow: 0.8 mL/min, λ = 254 nm, t_R = 13.5 min (major), 17.3 min (minor). ¹H NMR (500 MHz, CDCl₃) δ 7.99–7.84 (m, 4H), 7.57–7.49 (m, 4H), 7.48–7.42 (m, 4H), 7.38–7.33 (m, 4H), 7.26–7.19 (m, 2H), 7.09–7.01 (m, 4H). ¹³C NMR (126 MHz, CDCl₃) δ 197.2, 137.2, 136.6, 136.0, 134.0, 133.7, 132.3, 130.0, 128.2, 128.0, 127.6, 127.4, 127.2, 126.9, 125.6. HRMS (ESI) calcd for C₃₄H₂₃O₂ [M + H]⁺ 463.1693, found 463.1699.

3.1.2. General Procedure for the Synthesis of Target Compounds 3x–3aa

Under a nitrogen atmosphere, R’-MgBr (1.0 M, 0.60 mL, 0.60 mmol, 3.0 equiv) was added dropwisely to a solution of 1a or 1x (0.20 mmol, 1.0 equiv) in anhydrous THF (3.0 mL) at 0 °C. After being stirred at 25 °C for 4 h, the reaction was quenched with water (15 mL) and extracted with EtOAc (10 mL × 3). The combined organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated to afford the crude diol, which was used in next step without further purification.

Under a nitrogen atmosphere, sodium hypochlorite pentahydrate (99.3 mg, 0.60 mmol, 3.0 equiv) was added to a solution of the above crude diol and tetra(n-butyl)ammonium hydrogen sulfate (13.6 mg, 0.04 mmol, 20 mol%) in DCM (2.0 mL) and water (0.5 mL) at rt. After stirring for 1 h, the mixture was quenched with water (10 mL) and extracted with CH₂Cl₂ (15 mL × 2). The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE/EtOAc) to deliver the product 3x–3aa.

The reaction of 1x (69.2 mg, 0.20 mmol, 92% ee, 1.0 equiv) afforded product 3x (69.3 mg, 82%, 89% ee, S_T = 97%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 88.3 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel AD-H, isopropanol/hexane = 10:90, flow: 1.0 mL/min, λ = 210 nm, t_R = 16.4 min (minor), 30.8 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.81–7.75 (m, 4H), 7.43–7.37 (m, 2H), 7.30–7.26 (m, 4H), 7.26–7.22 (m, 2H), 7.05 (dd, J = 8.0, 1.0 Hz, 2H), 6.88 (dd, J = 8.5, 1.0 Hz, 2H), 3.48 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 196.4, 156.1, 139.7, 137.4, 132.2, 130.2, 128.0, 127.6, 124.3, 121.8, 112.8, 55.1. HRMS (ESI) calcd for C₂₈H₂₂O₄Na [M+Na]⁺ 445.1410, found 445.1414.

The reaction of 1a (62.8 mg, 0.20 mmol, 95% ee, 1.0 equiv) with EtMgBr (0.60 mmol, 3.0 equiv) afforded product 3y (58.2 mg, 85%, 95% ee, S_T = 100%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 1.52 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 2:98, flow: 0.8 mL/min, λ = 254 nm, t_R = 8.6 min (minor), 9.4 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.68–7.63 (m, 2H), 7.51–7.47 (m, 2H), 7.44 (d, J = 7.5 Hz, 1H), 7.39–7.34 (m, 2H), 7.34–7.29 (m, 2H), 7.27–7.25 (m, 1H), 7.25–7.22 (m, 1H), 2.80 (dq, J = 18.0, 7.0 Hz, 1H), 2.38 (dq, J = 18.0, 7.0 Hz, 1H), 2.03 (s, 3H), 2.01 (s, 3H), 0.91 (t, J = 7.0 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 203.9, 197.2, 139.5, 138.1, 138.01, 137.98, 137.6, 137.4, 136.8, 132.7, 132.6, 131.8, 130.2, 128.0, 127.2, 126.6, 126.1, 125.7, 33.9, 20.2, 20.0, 8.0. HRMS (ESI) calcd for C₂₄H₂₂O₂Na [M+Na]⁺ 365.1512, found 365.1519.

The reaction of 1a (62.8 mg, 0.20 mmol, 95% ee, 1.0 equiv) with 1-methylvinylmagnesium bromide (0.60 mmol, 3.0 equiv) afforded product 3z (53.9 mg, 76%, 96% ee, S_T = 100%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 7.06 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 2:98, flow: 0.8 mL/min, λ = 254 nm, t_R = 7.3 min (minor), 8.2 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.65–7.61 (m, 2H), 7.51–7.45 (m, 1H), 7.42 (dd, J = 7.5, 1.5 Hz, 1H), 7.38–7.34 (m, 2H), 7.34–7.32 (m, 1H), 7.30–7.26 (m 1H), 7.24–7.19 (m, 2H), 7.14 (dd, J = 7.5, 1.5 Hz, 1H), 5.38–5.34 (m, 1H), 5.25–5.21 (m, 1H), 2.11 (s, 3H), 2.09 (s, 3H), 1.69 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 199.1, 196.8, 143.9, 139.0, 138.8, 138.7, 137.9, 137.6, 137.1, 136.7, 132.5, 132.1, 131.4, 130.5, 130.1, 127.8, 127.1, 126.3, 126.13, 126.07, 20.12, 20.07, 17.3. HRMS (ESI) calcd for C₂₅H₂₂O₂Na [M+Na]⁺ 377.1512, found 377.1524.

The reaction of 1a (62.8 mg, 0.20 mmol, 95% ee, 1.0 equiv) with cyclopropylmagnesium bromide (0.60 mmol, 3.0 equiv) afforded product 3aa (53.2 mg, 75%, 94% ee, S_T = 99%) (eluent for column chromatography on silica gel PE/EtOAc = 10:1) as a white solid.${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ − 11.7 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel IC-3, isopropanol/hexane = 2:98, flow: 0.8 mL/min, λ = 254 nm, t_R = 30.1 min (minor), 35.8 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.71–7.66 (m, 2H), 7.59 (dd, J = 7.5, 1.5 Hz, 1H), 7.52–7.47 (m, 1H), 7.43 (dd, J = 7.5, 1.5 Hz, 1H), 7.39–7.34 (m, 2H), 7.34–7.29 (m, 2H), 7.29–7.24 (m, 2H), 2.22–2.16 (m, 1H), 2.03 (s, 3H), 2.02 (s, 3H), 0.97–0.91 (m, 1H), 0.91–0.85 (m, 1H), 0.84–0.78 (m, 1H), 0.56–0.47 (m, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 204.2, 197.1, 139.7, 139.3, 138.2, 137.6, 137.4, 137.1, 137.0, 132.6, 132.5, 132.0, 130.4, 128.0, 127.2, 126.9, 126.2, 125.8, 20.2, 20.1, 20.0, 12.4, 11.0. HRMS (ESI) calcd for C₂₅H₂₃O₂ [M + H]⁺, 355.1693, found 355.1687.

3.1.3. Preparation of 2,2′-dimethyl-6,6′-bis(1-phenylvinyl)-1,1′-biphenyl 4

Under a nitrogen atmosphere, a suspension of Ph₃PMeBr (535.8 mg, 1.5 mmol, 7.5 equiv) in THF (5.0 mL) was added to n-BuLi (2.4 M in hexane, 0.62 mL, 1.5 mmol, 7.5 equiv) at 0 °C (ice bath), and the mixture was stirred at 0 °C for 30 min to yield a yellow mixture. A solution of ketone 3a (78.0 mg, 0.20 mmol, 1.0 equiv) in THF (2.0 mL) was added at 0 °C. The reaction mixture was stirred at r.t. overnight. The resulting solution was quenched with aq. NH₄Cl and extracted with ethyl acetate (3 × 10 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated, and concentrated in vacuo, and the residue was purified by column chromatography on silica gel (PE/EtOAc = 20:1) to give 4 (66.4 mg, 86%, 93% ee).${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 321 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel IC, isopropanol/hexane = 0.1:99.9, flow: 0.8 mL/min, λ = 254 nm, t_R = 5.5 min (major), 8.1 min (minor). ¹H NMR (500 MHz, CDCl₃) δ 7.14 (dd, J = 7.5, 1.5 Hz, 2H), 7.12–7.05 (m, 4H), 7.05–6.99 (m, 4H), 6.83–6.79 (m, 4H), 6.79–6.76 (m, 2H), 5.16 (d, J = 1.5 Hz, 2H), 5.08 (d, J = 1.5 Hz, 2H), 1.55 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 150.4, 142.5, 141.6, 137.9, 137.2, 128.6, 128.0, 127.2, 126.8, 126.8, 126.5, 117.0, 19.7. HRMS (ESI) calcd for C₃₀H₂₇ [M + H]⁺ 387.2107, found 387.2125.

3.1.4. Preparation of 6,6′-dibenzoyl-[1,1′-biphenyl]-2,2′-dicarbaldehyde 5

Under a nitrogen atmosphere, a mixture of 3a (78.0 mg, 0.20 mmol, 1.0 equiv), benzoyl peroxide (24.2 mg, 0.10 mmol, 0.50 equiv) and NBS (356 mg, 2.0 mmol, 10 equiv) in CCl₄ (10 mL) was stirred for reflux for 8 h. After being cooled to r.t., the resulting solution was quenched with water, and the mixture was extracted with CH₂Cl₂ (3 × 5.0 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated, and concentrated in vacuo to give a crude product, which was used without further purification.

The mixture of the above benzyl bromide and AgNO₃ (552 mg, 2.0 mmol, 10 equiv) in CH₃CN (2.0 mL) and H₂O (1.0 mL) was stirred at 100 °C (oil bath) for 8 h. The resulting solution was cooled down and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 5 (51.1 mg, 61% for 2 steps, 93% ee).${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 7.02 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel AD-H, isopropanol/hexane = 20:80, flow: 1.0 mL/min, λ = 254 nm, t_R = 12.2 min (minor), 16.1 min (major). ¹H NMR (400 MHz, CDCl₃) δ 9.81 (s, 2H), 8.22–8.09 (m, 2H), 7.66–7.57 (m, 4H), 7.54–7.46 (m, 4H), 7.45–7.36 (m, 2H), 7.23–7.16 (m, 4H). ¹³C NMR (126 MHz, CH₂Cl₂) δ 195.6, 190.4, 138.8, 137.9, 136.8, 136.4, 133.6, 133.3, 130.3, 130.2, 128.2, 128.0. HRMS (ESI) calcd for C₂₈H₁₉O₄ [M + H]⁺ 419.1278, found 419.1281.

3.1.5. Preparation of (6,6′-dimethyl-[1,1′-biphenyl]-2,2′-diyl)bis(diphenylmethanol) 6

Under a nitrogen atmosphere, a mixture of 3a (78.0 mg, 0.20 mmol, 1.0 equiv) in THF (5.0 mL) was added to PhLi (1.0 M in ether, 0.80 mL, 0.80 mmol, 4.0 equiv) at 0 °C (ice bath), and the mixture was stirred at 0 °C for 30 min and rt for 3 h. The resulting solution was quenched with aq. NH₄Cl was extracted with ethyl acetate (3 × 10 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtrated, and concentrated in vacuo, and the residue was purified by column chromatography on silica gel (PE/EtOAc = 20:1) to give 6 (66.4 mg, 86%, 93% ee).${\left[\mathsf{\alpha }\right]}_{\mathrm{D}}^{20}$ + 116 (c 1.00, CH₂Cl₂). HPLC conditions: Chiralcel OD-3, isopropanol/hexane = 1:99, flow: 0.7 mL/min, λ = 230 nm, t_R = 6.9 min (minor), 9.3 min (major). ¹H NMR (500 MHz, CDCl₃) δ 7.30–7.18 (m, 20H), 7.13–7.08 (m, 2H), 6.91–6.86 (m, 4H), 4.72 (s, 2H), 0.74 (s, 6H). ¹³C NMR (126 MHz, CDCl₃) δ 148.9, 143.7, 143.2, 138.3, 138.2, 129.4, 128.8, 128.7, 128.0, 127.6, 127.5, 127.3, 126.8, 126.2, 84.3, 18.4. HRMS (ESI) calcd for C₄₀H₃₄O₂Na [M + Na]⁺ 569.2451, found 569.2460.

3.1.6. Free Radical Capture Experiment of 2a with TEMPO

Under an air atmosphere, a solution of 2a (39.2 mg, 0.10 mmol, 1.0 equiv) in THF (2 mL) was added to tBuOK (33.6 mg, 0.30 mmol, 3.0 equiv) and TEMPO (31.3 mg, 0.20 mmol, 2.0 equiv) at room temperature; then, the mixture was stirred at the same temperature for 30 min. A total of 0.5 mL of the reaction mixture was taken out and passed through a short pad of silica gel. The filtrate was analyzed by high-resolution mass. HRMS (ESI) calcd for C₃₇H₄₂NO₃ [M + H]⁺ 548.3159, found 548.3168; calcd for C₃₇H₄₁NO₃Na [M + Na]⁺ 570.2979, found 570.2992.

4. Conclusions

In conclusion, we have developed two sets of conditions for realizing oxidative C-C cleavage of dihydrophenanthrene-9,10-diols in the synthesis of axially chiral biaryl diketones. The merit of these two protocols is that the carbon–carbon bond cleavage ring-opening occurs under mild, metal-free conditions and in a very short reaction time, featuring a highly efficient point-to-axial chirality transfer process. Furthermore, the optically active diketones have been demonstrated to transform into an array of axially chiral compounds.

Author Contributions

L.S., J.Z. and B.H. performed the experiments and compounds’ characterization; L.S. and Z.G. conceived the idea and wrote the manuscript. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in the Supporting Information.

Acknowledgments

This work was supported by the University of Science and Technology of China, and Minjiang University.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Schemes and Table

Scheme 1. Asymmetric ring-opening for the synthesis of axially chiral biaryls. (a) Axially chiral biaryl synthesis via dynamic kinetic asymmetric ring-opening; (b) Chirality relay of Pd-catalyzed ring-opening of 8H-Indeno[1,2-c]thiophen-8-ols; (c) Chirality relay of ring-opening of α-hydroxy ketone or oxime ester; (d) This work: Chirality relay of ring-opening of optically active dihydrophenanthrene-9,10-diols.

Scheme 2. Substrate Scope. Conditions: tBuOK (0.60 mmol), air, THF (5.0 mL), 30 °C for 30 min; ST = ee3/ee1. b NaOCl·5H2O (0.60 mmol), n-Bu4NHSO4 (0.04 mmol), DCM (2.0 mL), H2O (0.5 mL).

Scheme 3. Control experiments.

Scheme 4. Plausible mechanism. (a) Plausible mechanism for tBuOK/air atmosphere system; (b) Plausible mechanism for NaClO/n−Bu4NHSO4 system.

Scheme 5. (a) Gram-scale reaction; (b) Synthetic applications.

Table 1

Optimization of reaction conditions ^a.

[Image omitted. Please see PDF.]
Entry	Atmosphere	Base	Yield/% c	Ee% d
1	O2	3.0 eq tBuOK	95	91
2 b	O2	3.0 eq tBuOK	85	94
3	Air	3.0 eq tBuOK	95	95
4	Air	2.0 eq tBuOK	56	92
5	Air	1.0 eq tBuOK	trace	-
6	Air	3.0 eq KOH	trace	-
7	Air	3.0 eq K2CO3	0	-

^a Conditions: i. 1a (0.10 mmol), PhMgBr (0.30 mmol), THF (2.0 mL), rt, 6 h; ii. Base (x mmol), THF (2.0 mL), rt, 10 min. ^b 0 °C. ^c Ioslated yield. ^d The ee values were determined by chiral-phase HPLC analysis.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28165956/s1. Experimental procedure, ¹H, ¹³C, ¹⁹F NMR spectra, and HPLC traces of the products (PDF); the single crystal structure of compound 2a and 3x (CIF).

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