Development of diverse adjustable axially chiral biphenyl ligands and catalysts

Summary Development of highly efficient and practical chiral ligands and catalysts is an eternal theme in asymmetric synthesis. Here, we report the design, synthesis, and evaluation of a new kind of adjustable axially chiral biphenyl ligands and catalysts, in which six model reactions including asymmetric additions of diethylzinc or alkynes to aldehydes in the presence of axially chiral [1,1′-biphenyl]-2,2′-diol ligands, palladium-catalyzed asymmetric cycloadditions in the presence of phosphoramidite ligands, and chiral phosphoric acid-catalyzed asymmetric synthesis of 1,1′-spirobiindane-7,7′-diol derivative and [4 + 3] cyclization were attempted. The results showed that variation of 2,2′-substituent groups could provide different types of ligands and catalysts, and adjustment of substituent groups at the 3,3′, 5,5′, 6,6′-positions could make ligands and catalysts more efficient in the asymmetric catalytic synthesis. Therefore, our present research should provide a new and useful strategy for development of diverse axially chiral ligands and catalysts.


RESULTS AND DISCUSSION
Synthesis of diverse axially chiral (S)-biphenyldiols and crystal structures of representative axially chiral (S)-biphenyldiols With our design above in hand, we first made the diverse biphenyldiols Supplemental information.

Addition of alkynes to aldehydes in the presence of ZnMe 2 and chiral biphenyldiols
To further explore application of our diverse adjustable chiral biphenyldiol ligands, we investigated Ti(O-i-Pr) 4 -catalyzed addition of alkynes to aldehydes in the presence of ZnMe 2 . Chiral propargylic alcohols are versatile synthons in organic chemistry, and catalytic asymmetric alkynylzinc addition to aldehydes can provide various chiral propargylic alcohols with high enantioselectivity. [42][43][44][45] As shown in Table 2, Ti(O-i-Pr) 4 -catalyzed addition of phenylacetylene (24a) to benzaldehyde (22a) was selected as the model reaction to test our ligands and (R)-BINOL in the presence of ZnMe 2 using dry dichloromethane (CH 2 Cl 2 ) as the solvent at 0 C (entries 1-12)), and (S)-L5 provided higher yield (85%) and highest ee value (93% ee) (entry 5). Other solvents, toluene, diethyl ether and THF, were attempted (entries 13-15), and they were inferior to DCM (entry 5). Subsequently, we surveyed substrate scope on the enantioselective addition of alkynes (25) to aldehydes (22). As shown in Figure 7, most of the tested aldehydes (22) and alkynes (25) afforded high yields and good to excellent ee values. During our screening, we found that addition of phenylacetylene (24a) to 3-bromobenzaldehyde only afforded 74% ee with (S)-L5 as the ligand. When (S)-L10 and (S)-L11 instead of (S)-L5 were used as the ligands, and 85% ee and 90% ee were obtained, respectively (see (R)-25t). The results also indicate that our diverse adjustable chiral biphenyldiol ligands are very useful for enantioselective regulation of different substrates. The reaction above can tolerate various functional groups including ether, cyano, CF 3 , NO 2 , C-F, C-Cl, C-Br bonds and S-heterocycle.
Pd-catalyzed asymmetric cycloadditions in the presence of chiral phosphoramidites Next, we investigated derivatization of our newly developed axially chiral biphenyldiol cores. It is well known that the phosphoramidites of axially chiral biaryldiols are the privileged ligands in the asymmetric synthesis. 46-51 At first, we prepared the BIPOL-derived phosphoramidite ligands according to previous procedures. 46-51 As shown in Figure 8A, reaction of chiral secondary amine 26 with PCl 3 in dry toluene provided 27, and treatment of 27 with our axially chiral biphenyldiols ((S)-L1, L2 or L3) gave the corresponding phosphoramidite ligands (S)-L14, L15 or L16 in 90%, 83% and 71% yields, respectively, for the two step reactions. Subsequently, we prepared chiral phosphoramidite ligand (S)-L18 in 56% yield via the similar procedures.
To evaluate reactivity and enantioselectivity of our newly developed chiral phosphoramidite ligands in asymmetric catalysis, two reactions were selected as the examples. Yang and Zhao reported the  (22)  iScience Article Pd-catalyzed [4 + 2] cycloaddition of benzofuran-derived azadienes with vinyl benzoxazinanones, and they found that cycloaddition of 30 with 31 in the presence of phosphoramidite ligand L12 provided high yield (92%) and ee value (92% ee). However, the reaction was incomplete when (S)-L13 was used as the ligand ( Figures 8B and 8C). 52 We attempted the cycloaddition of 30 with 31 in the presence of our chiral phosphoramidite ligands (S)-L14, L15 or L16. Inspiringly, (S)-L16 provided excellent diastereo-and enantioselectivity (>20:1 dr, 97% ee) ( Figure 8C). Subsequently, another example was surveyed. In 2014, Lu and Xiao developed the Pd-catalyzed asymmetric decarboxylation-cycloaddition of vinyl benzoxazinanones with sulfur ylides. 53 We investigated efficiency of the previous (S)-L17 and our newly developed (S)-L18 by using asymmetric decarboxylation-cycloaddition of 31 and 33, and the results showed that (S)-L18 was better than (S)-L17 in asymmetric reaction of 31 and 33b ( Figure 8D).

Conclusions
We have developed a new kind of diverse adjustable axially chiral biphenyl ligands and catalysts. Six model reactions were performed including asymmetric additions of diethylzinc or alkynes to aldehydes in the presence of axially chiral BIPOL ligands, Pd-catalyzed asymmetric cycloadditions in the presence of chiral phosphoramidite ligands, and chiral phosphoric acid-catalyzed asymmetric synthesis of 1,1 0 -spirobiindane-7,7 0 -diol (SPINOL) derivative and [4 + 3] cyclization to evaluate reactivity and enantioselectivity of our biphenyl ligands and catalysts. We found that variation of 2,2 0 -substituent groups could provide different types of ligands and catalysts, and variation of substituent groups at the 3, 3 0 , 5,5 0 , 6,6 0 -positions could make ligands and catalysts more efficient in the asymmetric catalytic synthesis. We believe that our newly developed diverse adjustable axially chiral biphenyldiols will find wide applications in enantioselective catalysis. The synthesis of ligands and catalysts needs many steps in this study, and more concise synthetic pathways are required.

Materials availability
This study did not generate new unique materials.
The chemicals used in this study were obtained from standard commercial suppliers and used as received.
Reactions were monitored by thin layer chromatography (TLC) and the products were obtained by column chromatography on silica gel. 1 H NMR, 13 C NMR, 19 F NMR and 31 P NMR were recorded on JEOL ECS-400 and were internally referenced to tetramethylsilane (TMS) and residual portion solvent signals (note: TMS referenced at 0.00 ppm; CDCl 3 referenced at 7.26 ppm and 77.16 ppm respectively; DMSO-d 6 referenced at 2.50 ppm and 39.52 ppm respectively). Data for 1 H NMR are reported as follows: chemical shift (d ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, dd = doublet of doublets, td = triplet of doublets, br = broad), coupling constant (J Hz). High-resolution mass spectra (HRMS) were recorded on FTICRMS BRUKER 7T and FTICRMS BRUKER 15T using matrix-assisted laser desorption ionization (MALDI-TOF) and LCMS-IT/TOF (SHIMADZU, Japan) with an electrospray ionization source (ESI-TOF). Chiral HPLC analysis was achieved using an Agilent 1100 Infinity series normal phase HPLC unit and Agilent Chemstation software. Daicel Chiralpak columns (250 3 4.6 mm) were used. Solvents were used of HPLC grade (Sigma Aldrich).

Data and code availability
d All data reported in this paper will be shared by the lead contact upon request. The crystallographic, catalysts and catalysis are provided in Supplemental Information as referenced in the main text. All original crystal structures have been deposited at CCDC and are publicly available as of the date of publication. CCDC numbers are listed in the key resources table.
d This paper does not report original code.
d Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

METHOD DETAILS
Synthesis of (S)-2,2'-bis(bromomethyl)-6,6'-dimethoxy-1,1'-biphenyl ((S)-3) To a solution of (S)-6,6'-dimethoxy-[1,1'-biphenyl]-2,2'-dicarbaldehyde ((S)-1) (50 mmol, 13.5 g) in EtOH (200 mL) was added NaBH 4 (125 mmol, 4.7 g) in portions at 0 o C, then allowed to warm to room temperature. After stirring for 8hat room temperature, the reaction mixture was cooled to 0 o C and added to aqueous NH 4 Cl solution slowly until no more gas was released. Then concentrated under reduced pressure, the mixture was extracted with EtOAc. The combined organic phase was washed with water, brine and dried over Na 2 SO 4 , filtered, and evaporated in vacuo, affording the target product (S)-2 as a white solid (13.4 g, 99% yield). The product was used for next step without further purification. To (S)-2 (30 mmol, 8.2 g) in CH 2 Cl 2 (DCM) (50 mL) was added a DCM (50 mL) solution of PBr 3 (75 mmol, 1.5 M) dropwise at 0 o C, the mixture was allowed to warm to room temperature after addition completed. After 5 h, the reaction mixture was put in ice bath and added to saturated Na 2 CO 3 aqueous solution dropwise. The mixture was extracted with DCM, the combined organic layers was washed with water, brine, dried over Na 2 SO 4 , filtered and concentrated in vacuum, affording the target product (S)-3.
To this flask was added (S)-L5 (0.1 mmol, 37 mg) and evacuated and back-filled five times with argon. Then Ti(O-iPr) 4 (0.125 mmol, 37 mL) in dry DCM (1 mL) was added by syringe subsequently. The mixture was stirred at room temperature for approximately 15 min to prepare the titanium complex. To another dry Schlenk tube was charged with alkyne (1.25 mmol), evacuated and back-filled five times with argon. Then a solution of 1M ZnMe 2 in toluene (1 mmol, 1 mL) was added by syringe at 0 o C with continued stirring for 15 min. The titanium complex was added via a syringe and the homogenous solution was stirred at 0 o C for 15 min. A solution of aldehyde (22) 2, 134.3, 131.9, 128.9, 128.5, 128.3, 122.3, 88.4, 87.1, 64.4 ppm.

OPEN ACCESS
General procedures for synthesis of (S)-42$45 To a solution of (S)-39 (3.63 g, 15 mmol) in DCM (50 mL) was added successively morpholine (7.8 mL, 90 mmol) and I 2 (9.5 g, 37.5 mmol) at room temperature. The mixture was stirred for 10 h. After that, 2 M HCl (50 mL) was added. The aqueous layer was extracted with CH 2 Cl 2 , and the combined organic layer was washed with saturated Na 2 S 2 O 3 solution and brine, and then dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by recrystallize in PE:DCM (50:1) to afford (