Chirality recognition of winding vine-shaped heterobiaryls with molecular asymmetry. Kinetic and dynamic kinetic resolution by Shi’s asymmetric epoxidation

The chirality of winding vine-shaped heterobiaryls with molecular asymmetry is recognized by a sugar-based chiral oxidant. Kinetic resolution of (±)-bisbenzoimidazole bearing an olefin moiety takes place with Shi’s asymmetric epoxidation to observe krel value up to ca. 35 affording the corresponding epoxide. The reaction of a (±)-bithiophene derivative also recognized the chirality to give the corresponding epoxide with er of 96:4 at 39% conversion. Dynamic kinetic resolution is found to take place when unsymmetrical biaryl composed of benzoimidazole/thiophene is subjected to Shi’s epoxidation, whose conversion of the racemic substrate exceeds to 50%.


Results and Discussion
We first examined to treat bisbenzoimidazole 1 with a chiral fructose-derived dioxirane, which is formed by the reaction of D-epoxone (2a) and oxone ® (KHSO 5 ·1/2KHSO 4 ·1/2K 2 SO 4 ), with which it was shown to afford the epoxide of a simple olefin developed by Shi and coworkers [26][27][28] . It was found that the chiral oxidant underwent enantiospecific epoxidation of 1. When bisbenzoimidazole (+)-(S a )-1 (>99% er) was subjected to the epoxidation reaction applying the standard conditions by Shi, oxidation of the olefin moiety of 1 proceeded smoothly and 50% of (+)-(S a )-1 was converted to the corresponding epoxide 3. The enantiopurity of 3 was confirmed as >99% er suggesting that no epimerization took place during the reaction 23 . On the other hand, the reaction of (−)-(R a )-1 under similar conditions hardly proceeded (3%) to recover the unreacted (R a )-1 (>99% er). (Scheme 1) These results show that chirality of the vine-shaped compound 1 recognize the chirality of sugar derivative 2a. The matched combination of (+)-(S a )-1 led to the epoxide 3 while mismatched (−)-(R a )-1 remained unreacted as shown in Fig. 2.
As such successful chirality recognition of the winding vine-shaped compound was in hand by Shi's epoxidation, the reaction was applied to the kinetic resolution of racemic (±)-1 as summarized in the table of Fig. 3 [29][30][31][32] . The reaction of 1 was carried out with 30 mol % of D-epoxone (2a) and oxone (2.7 eq) in the presence of 0.5 eq of NaB 4 O 7 ·10H 2 O in a mixed solution of acetonitrile and aq. Na 2 (edta) (1.5:1) for 24 h. Epoxide 3 was obtained at 22% conversion with the enantiomeric ratio of 86:14 accompanied by recovery of unreacted 1 (40:60 er) (entry 1). Shorter reaction periods resulted in a lower conversion whereas the enantiomeric ratio of the obtained epoxide was slightly higher. (entry 2) The reaction at lower temperatures was also found to proceed, however, further improved selectivity was not achieved (entry 3, 4) and stirring a longer period suggested little improvement in the selectivity. (entry 5) The reaction at 0 °C as well as at higher temperature for 24 h did not improve the %conversion value and the enantiomeric ratio of 3. (entry 6, 7). Switching the base to NaHCO 3 (15 equiv.) instead of K 2 CO 3 showed much higher selectivity but low conversion (21%). (entry 8) It was found important to perform the reaction in the presence of base, otherwise, no selectivity was observed at all(According to Shi's discussion on the asymmetric epoxidation, undesired decomposition of D-epoxone by Baeyer-Villiger oxidation takes place without K 2 CO 3 , which inhibits the progress of epoxidation. See: ref. 26 ). (entry 9) Indeed, increased amount of K 2 CO 3 resulted in giving improved enantiomeric ratio of 3 (entry 10 vs. 1). Use of increased amount of D-epoxone was also effective to result in a high enantiomeric ratio at 32% conversion (entry 11). The highest conversion with formation of a high degree of enantioselectivity of epoxide 3 was achieved when 0.6 eq of D-epoxone (2a) and 11.6 eq of K 2 CO 3 (95:5 er at 40% conv.: entry 12), accordingly. It was found that longer reaction period resulted in slight decrease of the enantiomeric ratio of 3. Non-enantioselective epoxidation by acetone, which was formed  by decomposition of D-epoxone, would occur along with the prolonged reaction periods. In the early stage of the reaction, the enantiomeric ratio of the obtained epoxide 3 was much higher. (entry [13][14][15][16][17] Employing the results on the reaction period of <5 min, the relative rate of the formation of 3 was estimated as k rel = 35.0. We then studied the use of chiral ketone in the kinetic resolution by asymmetric epoxidation. Figure 4 summarizes the employed ketones for the reaction. In addition to natural terpene (−)-menthone (2b) and (+)-camphor  Table of the results on kinetic resolution of racemic bisbenzoimidzole 1 by Shi's asymmetric epoxidation a . a The reaction was carried out with 0.1 mmol of rac-(±)-1 with oxone ® (2.7 eq), n Bu 4 NHSO 4 (4 mol %), and NaB 4 O 7 (0.5 eq) in CH 3 CN/aq. Na 2 (edta) (1.5:1 v/v). b The enantiomeric ratio (er) was determined by HPLC analysis with chiral column (DAICEL Chiralpak IF). c The reaction was carried out with NaHCO 3 instead of K 2 CO 3 in CH 3 CN/Na 2 (edta) aq.
Scientific REPORTS | (2018) 8:1704 | DOI:10.1038/s41598-018-19878-x (2c), chiral ketone 2d was prepared from D-glucose by following the literature procedure 33 . A fructose-derived chiral ketone bearing a different protective group was also prepared using cyclohexanone instead of acetone leading to cyclohexylidene derivative 2e 34 . As summarized in Fig. 5, use of 2b as a chiral ketone resulted in showing little rate difference between enantiomers at 29% conversion. (entry 2) Although the reaction with 2c as a chiral ketone proceeded smoothly to afford 90% of epoxide suggesting that both enantiomers were converted into epoxide. (entry 3) The glucose derived 2d was found to be converted into epoxide in 27% yield, however, little   Kinetic resolution was then subjected to several vine-shaped heterobiaryls (±)-4 in a similar manner as shown in Fig. 6. The reaction of tetrabromobisimidazole (±)-4a proceeded to afford epoxidation product 5a in a similar selectivity accompanied by formation of inseparable and unidentified by-products. Use of unsymmetrical heterobiaryl composed of benzoimidazole and dibromoimidazole (±)-4b 22 showed the similar selectivity to give 5b, however, the reaction also resulted to afford unidentified by-products. Kinetic resolution of heterobiaryl composed of benzoimidazole and benzene (±)-4c 22 was found to proceed smoothly to afford epoxide 5c at 53% conversion with er of 91:9 along with the recovered 4c (er = 4:96). It was also found that bithiophene (±)-4d underwent enantiospecific oxidation with D-epoxone (2a) leading to the corresponding epoxide 5d (87:13 er at 22% conversion). Slightly improved selectivity and conversion were achieved when oxidant bearing the cyclohexylidene moiety 2e was employed. The obtained epoxide (±)-5d exhibited 96:4 er at 39% conversion. Despite enantioselective consumption of (±)-4d to give 5d with a high enantiomeric ratio worthy of note is that the recovered bithiophene 4d was mostly racemic (45:55-50:50)(Racemization barrier was estimated by bithiophene 4d was experimentally estimated as 101.69 kJ mol −1 and calculated as 106. 15  The reaction was carried out 0.6 eq of chiral ketone 2, oxone ® (2.7 eq), n Bu 4 NHSO 4 (4.0 mol %), and K 2 CO 3 (11.6 eq) in CH 3 CN/aq. Na 2 (edta) (1.5:1 v/v) at 40 °C for 24 h. b The reaction proceeded to give epoxide 5a accompanied by inseparable and unidentified by-products. The ratio of 4a:5a was 50:50 by HPLC analysis. c The ratio of 4b:5b was 99:1 (with 2a) and 62:38 (with 2e), respectively, by HPLC analysis. results suggest that isomerization of recovered 4d to the racemate took place during enantioselective epoxidation reaction implying possible dynamic kinetic resolution [35][36][37][38] whereas conversion of the reaction did not exceed 50%. Accordingly, we surveyed structures of the winding-vine shaped biaryl that undergo racemization in a comparable rate to the Shi's oxidation under mild conditions. It was found that unsymmetrical heterbiaryl composed of benzoimidazole and another aromatic ring 22 . As depicted in Fig. 7, racemic heterobiaryl composed of benzoimidazole and thiophene (±)-4e was subjected to the epoxidation reaction with D-epoxone (2a). The reaction was found to proceed at 40 °C at 96% conversion after stirring for 24 h. The enantiomeric ratio of the obtained epoxide 5e was confirmed to be 83:17, which value exceeded the theoretical value in the case of non-dynamic resolution (52:48). The result suggests that racemization of 4e accompanies the Shi's epoxidation and thus showed that dynamic kinetic resolution of (±)-4e indeed took place.
In summary, we have shown that winding vine-shaped heterobiaryl with molecular asymmetry bearing an olefin moiety recognizes chirality of sugar-derived chiral ketone 2a and 2e to induce the rate difference between enantiomers of heterobiaryl. Kinetic resolution was thus achieved when a racemic heterobiaryl derivative was subjected to the conditions of Shi's asymmetric epoxidation. Heterobiaryl (±)-4 composed of imidazoles and thiophenes showed remarkable rate difference between enantiomers. It was also found that unsymmetrical biaryl bearing benzoimidazole/thiophene (±)-4e indicated dynamic kinetic resolution at the conversion to the epoxide exceeding to 50%.

Materials and Methods
All the reactions were carried out under nitrogen atmosphere. 1 H NMR (300, 400 MHz) and 13 C NMR (100, 125 MHz) spectra were measured on JEOL ECZ400, Varian Gemini 300, or Bruker Avance 500 spectrometer. Unless noted, NMR spectra were measured at room temperature. The chemical shift was expressed in ppm with CHCl 3 (7.26 ppm for 1 H), CDCl 3 (77.0 ppm for 13 C) as internal standards. High resolution mass spectra (HRMS) were measured by JEOL JMS-T100LP AccuTOF LC-Plus (ESI) with a JEOL MS-5414DART attachment. For thin layer chromatography (TLC) analyses throughout this work, Merck precoated TLC plates (silica gel 60 F 254 ) were used. Purification by HPLC with preparative SEC column (JAI-GEL-2H) was performed by JAI LC-9201. HPLC by chiral column was performed with JASCO LC-2000 Plus using DAICEL Chiralpak IC or IF (0.46 mm id, 25 cm length) with the flow rate = 1.0 mL/min unless noted. Chemicals were purchased and used without further purification unless noted. Bisbenzoimidazole 1 was prepared according to the procedure described in our previous report 19 . Separation of racemic 1 by preparative HPLC with chiral column was carried out with DAICEL Chiralpak IF (20 mm id, 25 cm length). L-Menthone and D-Camphor were purchased and used without further purification. D-epoxone was purchased from Alfa-Aesar Co. Ltd. Other chiral ketones for Shi's asymmetric epoxidation were prepared according to the reported procedures 33,34 . Tetrabromobisimidazole (±)-4a was prepared by the procedure in our previous report 23 . Unsymmetrical heterbiaryls (±)-4b, (±)-4c, and (±)-4e were prepared by the procedures in our previous report 22 . Bithiophene (±)-4d was prepared by the procedure described in our previous report 21 . Racemic epoxides 3 and 5d were prepared by epoxidation of (±)-1 and (±)-4d with m-chloroperbenzoic acid or oxone/acetone in a manner described previously 23   sodium acetate, and concentrated under reduced pressure to leave a crude oil. The enantioselectivity and conversion of the reaction was estimated by HPLC analysis with a chiral column (DAICEL Chiralpak IF) using hexane/ethanol = 1:1 as an eluent to show 50% conversion to 3 whose enantiomeric ratio was revealed as >99:1 (t R = 15.0 min).

Shi's asymmetric epoxidation of enantiopure bisbenzoimidazole (R a )-(-)-1. The reaction was car-
ried out in a similar manner under similar conditions as described above to result in 3% conversion by HPLC analysis with chiral column (DAICEL Chiralpak IF) to confirm recovery of unreacted (R a )-1 with e. r. of >99:1 (t R = 8.8 min) using hexane/ethanol = 1:1 as an eluent.
Kinetic resolution of racemic (±)-4d by Shi's epoxidation. The reaction was carried out in a similar manner for the resolution of (±)-1. When the reaction was carried out with chiral ketone 2e to undergo the reaction at 39% conversion. Epoxide 5d was obtained with er of 96:4, which was confirmed by HPLC analysis with chiral column. (DAICEL Chiralpak IF, eluent: hexane/ethanol = 100:1, t R = 10.9 and 11.9 min, flow rate = 1.0 mL/ min) with recovery of 4d as a mostly racemic mixture (ca. 50:50, t R = 12.0 min and 13.4 min, eluent: hexane, flow rate = 0.5 mL/min).