Enantioselective construction of ortho-sulfur- or nitrogen-substituted axially chiral biaryls and asymmetric synthesis of isoplagiochin D

Axially chiral biaryl motifs possessing ortho-heteroatom-substituted functionalities exist widely in the structures of natural products and have served as foundation for constructing prominent chiral organocatalysts, ligands, functional materials, and even bioactive molecules. However, a general and enantioselective synthesis of such chiral structures with high synthetic value is rare. Taking advantage of the BaryPhos-facilitated asymmetric Suzuki-Miyaura cross-coupling, we have established a general, efficient and enantioselective construction of the ortho sulfur- or nitrogen-substituted axially chiral biaryls. The protocol shows excellent compatibility to various functional groups and structural features, delivering chiral biaryl structures with ortho-sulfonyl groups or with ortho-nitro groups at a broad range of molecular diversity and complexity. The immobilization of BaryPhos on polyethylene glycol (PEG) support has enabled homogeneous enantioselective cross-coupling in aqueous media and the palladium catalyst recycling for multiple times. The method has enabled a concise 10-step asymmetric synthesis of isoplagiochin D as well as the construction of chiroptical molecules with circularly polarized luminescence (CPL) properties.


He Yang 1 & Wenjun Tang 1,2
Axially chiral biaryl motifs possessing ortho-heteroatom-substituted functionalities exist widely in the structures of natural products and have served as foundation for constructing prominent chiral organocatalysts, ligands, functional materials, and even bioactive molecules. However, a general and enantioselective synthesis of such chiral structures with high synthetic value is rare. Taking advantage of the BaryPhos-facilitated asymmetric Suzuki-Miyaura cross-coupling, we have established a general, efficient and enantioselective construction of the ortho sulfur-or nitrogen-substituted axially chiral biaryls. The protocol shows excellent compatibility to various functional groups and structural features, delivering chiral biaryl structures with ortho-sulfonyl groups or with ortho-nitro groups at a broad range of molecular diversity and complexity. The immobilization of BaryPhos on polyethylene glycol (PEG) support has enabled homogeneous enantioselective cross-coupling in aqueous media and the palladium catalyst recycling for multiple times. The method has enabled a concise 10-step asymmetric synthesis of isoplagiochin D as well as the construction of chiroptical molecules with circularly polarized luminescence (CPL) properties.
Axially chiral biaryl motifs exist in numerous natural products and endue these naturally occurring entities with different structural features and biological activities [1][2][3] . In medicinal chemistry, bioactive synthetic compounds based on axially chiral biaryl framework have been emerging as a promising class of drug candidates 4,5 . The chiral biaryl scaffolds also set up the foundation for chiral ligands/catalysts development, as exemplified by BINOL, BINAP, and related derivatives which have shown broad application in asymmetric catalysis 6,7 . Among chiral structures of this type, the ortho S-or N-substituted chiral biaryls are important and appealing, comprising a substantial proportion in alkaloids ( Fig. 1a) 8,9 . In addition, a series of chiral catalysts have been developed based on axially chiral biaryl skeletons with S-or N-substitution at the ortho position of the stereogenic biaryl axis, such as the chiral amino alcohol NOBIN and BINOL-derived disulfonimide catalysts [10][11][12] . In pharmaceutical industry, aryl sulfonyl groupcontaining compounds, such as sulfonamides, sulfones, and sulfonate, often display various biological activities and belong to a leading class of therapeutic agents. Nevertheless, most of these pharmaceutical compounds to date are achiral or with only central chirality 13 . Drug molecules bearing ortho-sulfonyl-substituted axially chiral biaryl scaffolds are rarely explored, but should be highly valuable since the three-dimensional topology exerted by axial chirality would impact their specificity and efficiency in protein binding 4,14 . Therefore, the development of practical and enantioselective synthetic method of c. Synthesis of axially chiral ortho S-or N-substituted biaryls via cross-coupling (this work) R  The asymmetric Suzuki-Miyaura cross-coupling has been a highly pursued method for the synthesis of axially chiral biaryl compounds. The last two decades have witnessed appreciable progress in this area, assisted by the development of a variety of prominent chiral ligands 15,16 . Despite the advancement, the employment of enantioselective Suzuki-Miyaura coupling in the synthesis of axially chiral natural products and high value-added molecules remains a challenging task and only a limited number of application have been reported to date [17][18][19][20][21] . In addition, synthetic and medicinal chemists nowadays still suffer from the situation of few readily available, practical and robust enantioselective cross-coupling protocols for the efficient synthesis of highly functionalized bioactive biaryl intermediates with axial chirality. The reported asymmetric Suzuki-Miyaura coupling methodologies are mostly restricted to the preparation of axially chiral biaryl products with ortho alkoxy, phosphonyl, alkyl, or amide groups. The ortho aldehyde-, ester-, amino-, and nitro-functionalized chiral biaryls which serve as precursors of chiral natural products and catalysts, have been seldom synthesized through this asymmetric crosscoupling method (Fig. 1b) [22][23][24] . Moreover, the biologically relevant ortho cyano-, alkenyl-, and sulfonyl-substituted axially chiral biaryls structures have never been synthesized via enantioselective Suzuki-Miyaura cross-coupling methods [25][26][27][28][29] .
Appealed by their remarkable synthetic utilities and potential biomedical applications, we herein report the enantioselective synthesis of ortho sulfonyl-substituted axially chiral biaryl compounds and the efficient construction of ortho nitro-substituted axially chiral biaryls with unprecedented molecular diversity and complexity via asymmetric Suzuki-Miyaura coupling (Fig. 1c). The post-transformations of these highly functionalized chiral structures have enabled a concise asymmetric synthesis of isoplagiochin D, a highly strained macrocyclic bis(bibenzyls) natural product, and CPL-active chiroptical molecules.

Results and discussion
The generality of BaryPhos-mediated enantioselective crosscoupling Noncovalent interactions between chiral ligands and substrates have been shown to be essential for catalytic asymmetric Suzuki-Miyaura cross-coupling 30,31 . Taking advantage of this tactic, we previously established the efficient synthesis of ortho-formyl-substituted axially chiral biaryls using BaryPhos, a P-chiral ligand containing a tertiary alcohol moiety as the hydrogen bond donor which could engage in hydrogen bonding with the CHO group of substrate and promote effective enantiocontrol in cross-coupling 18 . Structurally, substrates with functional groups bearing similar properties in charge distribution to aldehyde were presumed to comply with this catalytic mode. As shown in Fig. 2, a systematic evaluation of aryl bromide substrates carrying varied substituents ortho to the Br group demonstrated the feasibility of this concept and the rarely accessed ortho-ester (3a) and -nitro (3b) substituted axially chiral biaryls were synthesized in high yields and enantioselectivities from the coupling between the corresponding aryl bromides and boronic acids. This coupling protocol also enabled the highly enantioselective synthesis of axially chiral biaryl compounds possessing ortho-alkenyl (3c), cyano (3d), and sulfonyl functionalities (3e), demonstrating the generality and prominent enantio-induction ability of BaryPhos (see Supplementary Table 2 for ligands comparison).

Enantioselective synthesis of ortho sulfonyl-substituted axially chiral biaryls
The ortho S-substituted axially chiral biaryl compounds possess significant application potential in drug discovery and material science. However, their asymmetric synthesis remains a challenging task. Pioneering work from Colobert and co-workers enabled the efficient synthesis of ortho sulfinyl-substituted axially chiral biaryls via a sulfoxide-directed asymmetric C-H functionalization strategy 28,29 . Zhao and co-workers realized an electrophilic carbothiolation of alkynes for the synthesis of chiral sulfide-substituted vinyl arenes that could be converted to ortho S-functionalized axially chiral biaryls after posttransformation 27 . Besides these progresses, the development of efficient and general synthetic methods of ortho S-substituted axially chiral biaryl structures are still highly desirable. Fascinated by the important function of sulfonyl groups in drug molecules including enhancing potency and binding affinity, modulating solubility, and increasing metabolic stability, we attempted to realize the enantioselective synthesis of potentially valuable ortho-sulfonyl-substituted axially chiral biaryl molecules. Pleasingly, the Pd/BaryPhos-catalyzed asymmetric Suzuki-Miyaura cross-coupling was robust to provide a series of  axially chiral sulfones and sulfonamides in good yields and enantioselectivities at nearly ambient temperature (3f-i) (Fig. 3). Unprotected indolyl (3g) and quinolyl (3i) moieties were well-tolerated. The sulfonyl fluorides are highly desirable compounds in drug discovery and material science due to their 'clickable' characteristic in SuFex chemistry 32,33 . In addition, the propensity to undergo nucleophilic substitution renders them as versatile synthetic intermediates. Aryl bromides possessing ortho-fluoro sulfonyl functionality underwent smooth cross-coupling with substituted 1-naphthylboronic acids to afford axially chiral sulfonyl fluorides (3j-l) in excellent yields and enantioselectivities. It was noteworthy that tetra-ortho-substituted chiral biaryl 3m was synthesized with the current coupling protocol at elevated temperature. The coupling reaction was also compatible with various substrate skeletons, such as pyrenyl-(3n) and anthracenyl-(3r)    based boronic acids and the one possessing morpholine amide group (3q). Besides using naphthalene-type boronic acids, ortho-vinyl-substituted phenylboronic acid (3o) and carbazolyl boronic ester (3p) were suitable substrates and the reactions successfully delivered the corresponding coupling products. The post-functionalization of 3s led to a library of ortho sulfonyl-substituted axially chiral biaryl products. In specific, substitution reaction with hydroxyl and alkoxy nucleophiles provided axially chiral aryl sulfonic acid (3t) and 2,2,2-trifluoroethyl arylsulfonate (3u) in 88% and 96% yield, respectively. Treatment of 3s with n-hexyllithium or a C(sp 2 ) nucleophile provided chiral sulfones 3x or 3w in high yields, albeit with a slight loss in enantiomeric excess. The reaction between 3s and substituted lithium acetylide nucleophile gave 3v in 90% yield and 91% ee. Presumably, a nucleophilic substitution preceded initially followed by a subsequent Michael addition. Axially chiral sulfonyl fluoride 3s was also converted to chiral biaryl sulfonamide 3y in the presence of a lithium amide nucleophile.

Enantioselective synthesis of ortho nitro-substituted axially chiral biaryls
The immobilization of noble metal catalysts offers distinct advantages, such as adjustable solubility of catalyst, ease of catalyst separation, and recycling 34,35 . In the enantioselective synthesis of ortho-nitro-substituted axially chiral biaryls, a PEG 2000 -bound BaryPhos was developed, enabling the asymmetric Suzuki-Miyaura coupling to proceed in water. A serial of axially chiral biaryl products possessing ortho-nitro and -methoxy groups were fashioned in high yields and ee's (6a-d, 6o) (Fig. 4). The absolute configuration of 6a was determined by single crystal X-ray diffraction. Chiral biaryls bearing fluorine atom at the ortho position were also synthesized efficiently (6e-g). Highly functionalized aryl bromides could also serve as suitable substrates and 6h containing substituted pyrrole ring was afforded in 80% yield and 88% ee, while 6i with an aminoindanol pendant was produced in 64% yield and 93% de. It should be noted that the naphthalene ring was not a necessity for the current enantioselective cross-coupling, as the reaction between aryl bromides and ortho vinyl-substituted phenylboronic acids led to chiral biphenyls (6j-m, 6p) and pyrrolyl-phenyl coupling product 6n with excellent stereochemical fidelity. Functional groups including aldehyde (6j, 6n) and piperidine ring (6p) were well tolerated. The coupling reaction was also compatible with 2-styryl-and difluorovinyl-substituted phenyl boronic acid derivatives to give enantioenriched axially biaryl products 6q and 6s. Variation of the ortho-methoxy unit within aryl bromide to a methyl group (6r) had little influence on the reactivity and enantioselectivity of the reaction. With respect to the sterically demanding cross-coupling for the synthesis of tetra-ortho-substituted biaryl 6t, a higher temperature (70°C) was required to maintain consistent reactivity, while a slightly diminished enantioselectivity was observed. The transformation of these coupling products was straightforward and reduction of nitroarene 6o by Zn delivered axially chiral amine 6v in 88% yield and no erosion of ee value was observed. Additionally, chiral biphenyl 6u underwent a hydroboration-oxidation sequence to give an alcohol intermediate which was converted to axially chiral acid 6w upon treatment with RuCl 3 /NaIO 4 . The recyclability of the catalyst with PEGsupported chiral ligand was demonstrated in the cross-coupling of 4a and 5g. Benefited from the sharply different solubility of hydrophilic catalyst in H 2 O and Et 2 O, the supported catalyst was reused readily by recycling the aqueous phase, while product 6u and trace amounts of starting materials was separated by extraction with Et 2 O. The Pd catalyst supported by PEG 10000 -BaryPhos was used for four cycles to provide good yields (>80%) and steady enantioselectivity (93-94% ee). Further recycling operations led to a slight decrease in yield and ee of 6u (77% yield and 89% ee after 4 runs), which was presumed due to Pd leaching or gradual catalyst loss during the recycling process.
Open-chain to macrocyclic axial chirality conversion  Enantioselective synthesis of isoplagiochin D Having established an efficient synthesis of ortho-sulfonyl and -nitrosubstituted axially chiral biaryls, the application of this general crosscoupling protocol was explored in the asymmetric synthesis of isoplagiochin D, a cyclophane-type natural product containing an axially chiral di-ortho-substituted biphenyl unit embedded in its strained macrocycle. Previous asymmetric synthesis of this macrocyclic bis(bibenzyls) molecule using an asymmetric macrocyclization 36 or Heck reaction 37,38 suffered from either unsatisfactory yields or enantioselectivities (Fig. 5a). We presumed that the axial chirality could be generated prior to the macrocyclic ring closure by using a highly enantioselective cross-coupling, and the obtained tri-ortho-substituted axially chiral biaryl intermediate possessing a removable group such as NO 2 , could be elaborated as the chiral di-ortho-substituted biphenyl moiety (Fig. 5b). Macrocyclic ring closure followed by removal of the nitro group would unambiguously furnish the key chiral di-orthosubstituted biphenyl unit. With this concept, our asymmetric synthesis commenced with the preparation of aryl bromide 9 from the Horner-Wadsworth-Emmons reaction between the known aldehyde 8 and phosphonate derivative of 7 (Fig. 6). A subsequent Miyaura borylation converted 9 to boronic ester 10 in 83% yield. In the presence of Pd/ (S,S)-BaryPhos catalyst, the enantioselective Suzuki-Miyaura crosscoupling of 10 bearing a complex structural skeleton and multifunctionalized 11 furnished chiral biaryl 12 in 70% yield and 90% ee, demonstrating the practicality and robustness of this atroposelective coupling protocol. The tri-ortho-substituted biaryl 12 served as the chiral foundation of the synthesis and was transformed to chiral intermediate 13 under homogeneous hydrogenation using Wilkinson catalyst. It was noteworthy that both the alkene moiety and the more electron-deficient aldehyde group was reduced, which enabled the synthesis of phosphonate 14 after iodination of 13 and subsequent phosphonation. An intramolecular Horner-Wadsworth-Emmons reaction afforded an inseparable Z/E isomeric mixture of macrocycle 15 whose alkene group was reduced via catalytic hydrogenation. Under the same condition, the nitro functionality was converted to an amino group which was finally removed by reductive deamination (NaNO 2 , H 3 PO 2 ), giving rise to 16 in 46% yield over three steps. A final demethylation afforded isoplagiochin D with M configuration in 87% yield.
To the best of our knowledge, this 10-step asymmetric synthesis of isoplagiochin D represents an example of building strained axially chiral cyclophane-type natural products from an open-chain chiral biaryl precursor and this efficient strategy should be valuable for the synthesis of macrocycles possessing axially chiral biaryl subunit.

Photophysical properties investigations
In recent years, the development of chiroptical structures displaying CPL properties has been an attractive area and chromophores based on axially chiral framework have received significant attention 39,40 . The three-dimensional orientation of these molecules endows them with unique photophysical properties at both ground and emitting excited states. Benefited from the convenient synthesis of enantioenriched 3n through asymmetric cross-coupling, the post-functionalization of this entity led to pyrenyl containing compounds P-17 and P,P-18 (Fig. 7a)   crystal X-ray diffraction and a strong π-π stacking interaction between the two pyrenyl rings was observed in the solid state. Under UV light irradiation (365 nm), the solution of 17 in CH 2 Cl 2 exhibited cyan luminescence, while 18 displays bright green luminescence (Fig. 7b). Both compounds show similar UV-vis spectra ranging from 220-350 nm while an additional broad absorption peak was found for 18 at 435 nm due to its extended π system (Fig. 7c). The emission maxima in dilute dichloromethane were recorded at 492 nm and 495 nm for 17 (Φ = 0.49) and 18 (Φ = 0.73), respectively. Strict mirror images were observed for the circular dichroism (CD) spectra of M-17/P-17 and M,M-18/P,P-18, displaying clear cotton effects at several wavelengths (Fig. 7d, e). It was delighting that both pairs of enantiomers M-17/P-17 and M,M-18/P,P-18 are CPL-active. In particular, M-17 emits intense positive CPL signals ranging from 420 nm to 550 nm, while P-17 displays a negative signal within the same region (Fig. 7f). In addition, the luminescence dissymmetry factor (g lum ) of 17 was measured as high as 9.3 × 10 −3 (Fig. 7g). These chiroptical properties demonstrated the high application potential of related axially chiral molecules in developing new organic chiroptical functional materials.
In this work, a general, efficient and enantioselective synthesis of the ortho sulfur-or nitrogen-substituted axially chiral biaryls has been established by a Pd/BaryPhos-catalyzed Suzuki-Miyaura cross-coupling. The versatile protocol shows excellent compatibility to various functional groups and structural features, delivering chiral biaryl structures with ortho-sulfonyl groups or with ortho-nitro groups at a broad range of molecular diversity and complexity. The development of PEG 10000 -BaryPhos has allowed the asymmetric cross-coupling to proceed in aqueous media and the palladium catalyst recycling for multiple times. Additionally, the method has enabled a concise 10-step asymmetric synthesis of isoplagiochin D as well as the construction of chiroptical molecules with CPL properties, demonstrating its high synthetic values and application potential in natural product synthesis, medicinal chemistry, and material science.

Methods
General procedure for asymmetric Suzuki-Miyaura coupling To a mixture of aryl halide or triflate (0.20 mmol), arylboronic acid or arylboronic ester (0.30 mmol), base (0.60 mmol), Pd 2 (dba) 3 (1.0 μmol) and chiral ligand (2.0 μmol, Pd/ligand mol ratio: 1/1) under N 2 was charged degassed solvent. The mixture was stirred at noted temperature for noted time. Ethyl acetate (15 mL) was added and the organic phase was washed sequentially with water (5 mL) and brine (5 mL). The organic layer was separated, dried over Na 2 SO 4 , filtered and concentrated. The crude enantioenriched chiral biaryl product was purified by silica gel flash column chromatography. A mixture of DCE/H 2 O (5:1) was used as solvent and K 3 PO 4 as the base for sulfonyl-substituted substrates and the reaction was conducted at 35°C for 48 h unless otherwise specified. H 2 O was used as solvent and K 2 CO 3 as the base for nitro-substituted aryl bromide substrates and the reaction was conducted at 30°C for 12 h unless otherwise specified.

Data availability
The data that support the findings of this study are available within the paper and its supplementary information files. Source Data of photophysical property studies are provided with this paper. Materials and methods, experimental procedures, characterization data, 1H, 13 C, 19 F NMR spectra and mass spectrometry data are available in the Supplementary Information. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Center (CCDC), under deposition numbers CCDC 2130064 (6a), and CCDC 2130065 (P-17). These data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif. Source data are provided with this paper.