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

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.


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

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 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.

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). 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 ST (defined as the ee value of the product divided by the ee value of the starting material, ST = 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).

Entry
Atmosphere 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 = ee 3 /ee 1 × 100%) remained consistently high (96-100%), regardless of the electronic effect of the paraor metasubstituents, 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 cyclopropylsubstituent were unreactive in the presence of tBuOK under an air atmosphere. However, the ring-opening reaction with sodium hypochlorite under n-Bu 4 NHSO 4 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 O 2 or anion radical O 2 − ·. In our previous studies, the possible radical intermediate was trapped by DMPO and analyzed by elec- tron 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).
Molecules 2023, 28 It was found that 2x remained inert in the presence of tBuOK under an air atmo phere. In order to eliminate the possibility of the electronic effect caused by the tw methoxy groups, diol 2bb was synthesized, and it also exhibited poor reactivity und the identical conditions (Scheme 3). This suggests that, in fact, the torsional strain of di may actually be conducive to its C-C bond cleavage. 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.

Scheme 3. Control experiments.
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).
Scheme 4. Plausible mechanism. (a) Plausible mechanism for tBuOK/air atmosphere system; (b) Plausible mechanism for NaClO/n−Bu4NHSO4 system 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 AgNO3, 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]. Scheme 4. Plausible mechanism. (a) Plausible mechanism for tBuOK/air atmosphere system; (b) Plausible mechanism for NaClO/n−Bu 4 NHSO 4 system.
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].

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
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].

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 Na 2 SO 4 , 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.
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 CH 2 Cl 2 (15 mL × 2). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered, and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE/EtOAc) to deliver the product 3x-3aa.