Enantioselective aza-Friedel–Crafts reaction of furan with α-ketimino esters induced by a conjugated double hydrogen bond network of chiral bis(phosphoric acid) catalysts

Chiral C2- and C1-symmetric BINOL-derived bis(phosphoric acid) catalysts facilitated the enantioselective aza-Friedel–Crafts reaction of 2-methoxyfuran with α-ketimino esters.

acidic layer was concentrated under reducued pressure, and extracted with dichloromethane (20 mL × 2) and washed with 1 M HCl aqueous solution (10 mL). The resulting organic layer was concentrated under reduced pressure. The obtained product was dissolved in toluene (20 mL), and the volatiles were thoroughly removed under reduce pressure. The product was dissolved in dichloromethane (10 mL), and the excess amount of n-hexane was added to give of (R)-5a as a white-yellow powder (3.02 g, 88% yield). A trace amount of Et 2 O remained. 1

Method A
Preparation of (R)-S10a: A solution of chiral diol (R)-S9a 3 (1.67 g, 3.25 mmol) and sodium hydride (ca. 60%w/w oil dispersion, 400 mg, 9.9 mmol) in THF (33 mL) was stirred at 0 °C for 3 h under a nitrogen atmosphere. Diallyl chlorophosphate 2 (1.30 mL, 7.9 mmol) was slowly added at 0 °C, and the mixture was stirred at room temperature for 9 h. The resulting mixture was then cooled in ice bath, and diluted with ethyl acetate (20 mL) and water (10 mL). The product was extracted with ethyl acetate (10 mL × 2) and washed with brine (10 mL). The combined extracts were dried over Na 2 SO 4 . The organic phase was concentrated under reduced pressure, and the crude was roughly purified by short silica gel column chromatography (eluent: n-hexane:EtOAc = 5:1). Impure (R)-S10a was obtained in ca. 75% yield (2.0 g).
Preparation of (R)-9a: Pyrrolidine (430 µL, 5.3 mmol) and tetrakis(triphenylphosphine)palladium (0) (1.1 g, 0.96 mmol) was added to a solution of (R)-S10a (impure, 2.0 g, 2.4 mmol) in N,N-dimethylformamide (24 mL) at 0 °C. The reaction mixture was stirred at room temperature for 5 h. The solution was put onto a column with the anion exchange resin (DOWEX Clform. See below for the preparation of the resin), which was prepared in advance. The sample-mounted resin was washed with THF (300 mL). Then THF and 12 M HCl aqueous solution (v/v = 10/1, 500 mL) was passed through the resin, and the filtrate was collected. The acidic layer was concentrated under reduced pressure, and extracted with dichloromethane (20 mL × 2) and washed with 1 M HCl aqueous solution (10 mL). The resulting organic layer was concentrated under reduced pressure. The obtained product was dissolved in toluene (20 mL), and the volatiles were thoroughly removed under reduced pressure. The product was dissolved in dichloromethane (10 mL), and the excess amount of n-hexane was added to give pure (R)-9a as a white-yellow powder (0.924 g, 42% yield in two steps).
Instead, we obtained a suitable crystal of racemic-10c. By X-ray analysis, we unambiguously confirmed the structure of 10c (Fig. S3), in particular, the position of the i-Pr moiety. The other possible isomer (R)-10c' was not obtained in our preparation, probably due to steric constraints of the bulky aryl moiety at the 3-position of the binaphthyl of (R)-S13c (Fig. S2). Racemic-10c does not have a conjugated intramolecular double hydrogen bond network as seen for (R)-5c•(pyridine) 2 in     β,γ-Alkynyl-α-imino esters 1: Ketoesters S14 were prepared based on the reported procedures. [4][5][6] Compounds 1 were prepared on the basis of a literature procedure. 7 To a well-dried round bottom two necks flask (50 mL) with ketoester S14 (5.0 mmol) and N-Cbz-triphenyliminophosphorane 8 (2.06 g, 5.0 mmol) was added toluene (10 mL). The mixture was heated to 120 °C and stirred for 6 h. After cooling to room temperature, volatiles were removed under reduced pressure. The resultant residue was purified by MPLC (eluent: n-hexane:EtOAc = typically 100:0 to 80:20) to give the desired product 1.  0.40 mmol) was added and the mixture was stirred at -78 °C for 24 h. To quench the reaction, silica gel (4 mL) was added to the mixture at -78 °C. The resultant silica gel was thoroughly washed with n-hexane and ethyl acetate (3:1, 200 mL) at room temperature. The filtrate was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluent: n-hexane:EtOAc = 5:1 to 3:1) to give the product 3b (85.3 mg, 83% yield). The catalyst could be recovered as some metal (Li, Na, K, Ca, etc.) salts of (R)-5b through the same silica gel column chromatography (eluent: CHCl 3 :MeOH = 3:1) quantitatively. When the catalyst would be reused for the catalysis, the further purification with washing by 1 M HCl aqueous solution is necessary (>99% recovery). The enantiomeric purity of 3b was determined by chiral HPLC analysis (91% ee).

S21
n-hexane and ethyl acetate (3:1, 400 mL) at room temperature. The filtrate was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography (eluent: n-hexane:EtOAc = 5:1 to 3:1) to give the product 3b (1.89 g, 77% yield). The catalyst could be recovered as some metal salts of (R)-5b through the same silica gel column chromatography (eluent: CHCl 3 :MeOH = 3:1) quantitatively. When the catalyst would be reused for the catalysis, the further purification with washing by 1 M HCl aqueous solution is necessary (>99% recovery). The enantiomeric purity of 3b was determined by chiral HPLC analysis (91% ee).

Screening of achiral catalysts in the probe reaction of 2 with 1a.
The screening of achiral catalysts in the probe reaction of 2 with 1a is summarized in Table   S1. The pK a values of the acid compounds used here are generally available in the literature. The desired product 3a was obtained in better yield and chemoselectivity by catalysts, particularly some carboxylic acids such as CHF 2 CO 2 H and CCl 3 CO 2 H (entries 3 and 4), with pK a values of 2.5-6.5 in DMSO and 0.65-1.24 in H 2 O. The pK a range was comparable to the pK a values of phosphoric acids (entries 10 and 11).

Screening of chiral catalysts in the probe reaction of 2 with 1a.
Screening of chiral catalysts in the probe reaction of 2 with 1a is summarized in Scheme S1.
Scheme S1 Screening of the catalysts in the probe reaction of 2 with 1a.

Screening of chiral catalysts in the probe reaction of 2 with 1b.
Substrate 1b was much less reactive than 1a. Therefore, the screening of chiral catalysts in the probe reaction of 2 with 1b was examined again (Scheme S2). As a result, the catalytic activities of conventional chiral phosphoric acids (R)-4a and (R)-4b were low. An increase in the amount of (R)-4b from 5 mol% to 10 mol% slightly improved both the yield and the enantioselectivity.

Scheme S2
Screening of the catalysts in the probe reaction of 2 with 1b.

Calculation of the electrostatic potential of phosphoric acids.
An effective approach to estimating molecular pK a values from simple density functional calculations has been developed by Liu. 14 Various compounds show a strong correlation between experimental pK a values and molecular electrostatic potential (MEP). As a result of their research, a linear relationship between the MEP and experimental pK a values has been established.
Therefore, we performed preliminary theoretical calculations using Spartan'10 for Macintosh from Wavefunction, Inc. (Fig. S5 and Table S2). The geometries of S20-S26 were optimized with gradient-corrected density functional theory (DFT) calculations with B3LYP using the 6-31+G* basis set, after MMFF (molecular mechanics) and HF/3-21G (ab initio molecular orbital method) calculations. We first investigated the MEP values of simple compounds S20 and S21, which have known pK a values (pK a = 0.26 15 for S20 and 1.42 16 for S21). As a result, a higher MEP value was observed in S20 than in S21, and our preliminary calculations for these model compounds may support a relationship between pK a and MEP values.

S26
First, we investigated the effect of external hydrogen bonding in S22 and S23, which involves one hydrogen bonding between two molecules of S20 and two hydrogen bondings between two molecules of S21, respectively. Also, we observed a higher value of MEP (75.2 kcal/mol) for S23 than for S21 (69.0 kcal/mol). These results should clearly support the idea that appropriate hydrogen bonding between two molecules of phosphoric acids would increase the Brønsted acidity.
Next, we investigated the effect of two internal hydrogen bondings in S24 as a simple model of (R)-5. As a result, we observed a higher value of MEP (78.0 kcal/mol) for cyclic S24 than for acyclic S23 (75.2 kcal/mol), although S23 and S24 have different ester moieties. Moreover, the MEP value for S25 (75.9 kcal/mol) as a model of (R)-10 was lower than that for S24. Moreover, the MEP value for S26 (76.5 kcal/mol) as a model of (R)-4 was lower than that for S24 (78.0 kcal/mol). Accordingly, (R)-5 might be expected to be more acidic than (R)-4, and (R)-10 might be expected to be less acidic than (R)-4 as shown in Fig. S6.
It should be noted that the estimated order in Fig. S6 does not involve steric factors of the catalysts (also see Fig. S9).

Optimization of the concentration, drying agents, solvents, and substrates in the reaction of 2 with 1.
The effects of the concentration of substrate 1b and drying agents were examined (Table S3).
As a result, 0.1 M (based on 1b) conditions showed better enantioselectivity than 0.05 M and 0.2 M (entries 1-3). The drying agent used did not significantly affect the enantioselectivity, but did affect the reactivity (i.e., the reaction time for full conversion) and chemoselectivity for unknown byproducts, which might be triggered by the reaction of water with 1b and/or 2 (entries 4-7). As a result, MS 5Å was better than MS 3Å, MS 4Å, and MgSO 4 . Next, the general solvent effect was examined (Table S4). As a result, polar solvents were not suitable at all, and dichloromethane was much better than the other solvents tested. The reaction temperature was also examined (entries 7-9), and a lower temperature gave higher enantioselectivity (92-94% ee), although the yields were decreased (46-52%).

S32
Next, β,γ-alkynyl-α-imino esters 1 were optimized with the use of (R)-5b (Table S5). To avoid the effect of adventitious water, which might react with 1 and 2 to give undesired products, powdered MS 5Å was used as a drying agent. As a result, the reaction of 2 with 1a (R 1 = Ph CO 2 R 2 = CO 2 Et, CO 2 R 3 = Cbz) proceeded smoothly, and a slightly better result (88% yield and 76% ee) was observed (entry 1). Next, we changed the terminal R 1 group of the acetylene from a Ph group to sterically hindered silyl groups (entries 2-6). As a result, the enantioselectivity of the corresponding product 3 was improved according to the bulkiness of the silyl group (also see a possible transition state on page S72). Ultimately, when we used 1b (R 1 = i-Pr 3 Si, CO 2 R 2 = CO 2 Et, CO 2 R 3 = Cbz) with a bulky i-Pr 3 Si group, 3b was obtained in 83% yield with 91% ee (entry 6). The ester groups CO 2 R 2 and C=NCO 2 R 3 in 1 were also optimized. However, we did not find better ester groups to replace CO 2 Et for CO 2 R 2 and Cbz for CO 2 R 3 (entries 7-10). Based on these results, we selected 1b (R 1 = i-Pr 3 Si, CO 2 R 2 = CO 2 Et, CO 2 R 3 = Cbz) as an optimized catalyst for this reaction.

Preparation of (R)-6 (Scheme 1).
To a solution of (R)-5b ( The obtained product (R)-S27 would be used in the next step without further purification.
(R)-S27 was dissolved in methanol (2 mL) and the solution was stirred at room temperature for 4 h. Excess mthanol was then removed in vacuo. The obtained product was dissolved in toluene (2   mL  S34 stirred at 40 °C for 5 min. Then oxalyl chloride (15 µL, 0.175 mmol) was added at room temperature, and the mixture was warmed to 40 °C. The mixture was stirred at 40 °C for 5 min.
Volatiles were removed in vacuo under heat conditions (ca. 40-50 °C). The obtained product (R)-S28 would be used in the next step without further purification. (R)-S28 was dissolved in mixed solvent of dichloromethane (2 mL) and methanol (4 ml) the solution was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: CHCl 3 :MeOH = 8:1 to 1:1) to give (R)-6b, which would be contaminated with alkali and alkali earth metal ions. The obtained (R)-6b was dissolved in dichloromethane, and throughly washed with 1 M HCl aqueous solution, and the organic phase was separated. After the removal of volatiles under reduced pressure, the residue was dissolved in toluene, and the volatiles were thoroughly removed under reduced pressure to give pure (R)-6b as white-yellow solid (87%, 86.1 mg). Summary of the reaction with the use of (R)-5b, (R)-6a, and (R)-6b is shown in Scheme S3.

Scheme S3
Role of Brønsted acid in the catalysts. 15. Non-linear effect in the reaction of 2 with 1a (Fig. 3).
The presence of a non-linear effect was examined in the reaction of 2-methoxyfuran 2 (0.80 mmol) with α-ketimino ester 1a (0.40 mmol) in the presence of (R)-5b (5 mol%, 0% ee to 100% ee) in dichloromethane (0.1 M based on 1a) at -78 °C for 6 h. As shown in Scheme S4, a non-linear effect was not observed. Moreover, the yields of (S)-3a were independent of the enantiopurity of (R)-5b, and (S)-3a was obtained in a consistent yield of 71-75%. Therefore, a possible active species might be the monomeric structure of (R)-5b.
We also examined the reaction of 2 with 1a in the presence of (R)-4a or (R)-4b (5 mol%, 0% ee to 100% ee) in dichloromethane (0.1 M based on 1a) at -78 °C (Schemes S5 and S6). The reaction time was 12 h for (R)-4a catalysis, and 6 h for (R)-4b catalysis. As shown in Scheme S5, a positive non-linear effect was observed for (R)-4a-catalysis. This result strongly suggests that (R)-4a-catalysis might involve the dimeric structure of (R)-4a. In contrast, as shown in Scheme S6, a non-linear effect was not observed for (R)-4b-catalysis. This result strongly suggests again that a possible active species might be the monomeric structure of (R)-4b. The P=O moiety of (R)-4b is much less basic than (R)-4a, and therefore, the dimeric structure might not be involved in (R)-4b catalysis.
As a result, the ESI-MS (negative) analysis of S20 in CH 2 Cl 2 /MeOH/CH 3 CN = 2/1/1, as shown in Fig. S7a, clearly suggests that S20 would not be a monomer. Instead, a dimer, trimer, tetramer, 5-mer, and 6-mer were observed under polar solvent conditions. (R)-S15 as shown in Figs. S5b would be a monomer, but a dimer, trimer, and tetramer were also observed as major species. In sharp contrast, the population of dimer, trimer, and tetramer of (R)-S3 in CH 2 Cl 2 /MeOH/CH 3 CN = 2/1/1 was reduced, as shown in Fig. S7c. Next, we used CH 2 Cl 2 alone for highly soluble (R)-S3, as shown in Fig. S7d. As a result, a trimer and tetramer were not observed and the population of dimer was greatly decreased. Less polar solvents might be favored for hydrogen bonding, and the intramolecular double hydrogen bond network might be maintained under CH 2 Cl 2 solvent conditions. Moreover, much more sterically hindered (R)-5b and (R)-10c in CH 2 Cl 2 gave spectra (Figs.S5e and S5f) that were quite similar to that in Fig. S7d. Overall, this ESI-MS analysis suggests that bis(phosphoric acid)s, such as (R)-S3, (R)-5b, (R)-10c, would remain mostly as a monomer, whereas phosphoric acids, such as S20 and (R)-S15, would easily exhibit dimer, trimer, and tetramer forms. Overall, Fig. S8 summarizes the possible aggregation of the catalysts S20, (R)-S15, (R)-5b, and (R)-10c.
The correlation between the possible acidity (see Table S1, and Figs. S5 and S6), aggregation (see Figs. S7 and S8), and catalytic activity (see Table S1 and Scheme S1) of the catalysts is shown in Fig. S9. Catalyst (R)-5b might have much better Brønsted acidity than the others, and might avoid aggregation due to neutralization of the highly Brønsted basic P=O moiety through the conjugated double hydrogen bond network. As a result, catalyst (R)-5b would show better results than the others.   Dimer of (R)-S15
After 5 min, α-ketimino ester 7 (0.20 mmol) in dichloromethane (1 mL), and 2-methoxyfuran 2 (37 µL, 0.40 mmol) were added at -78 °C. The reaction mixture was allowed to warm to -60 °C and was then stirred at that temperature for 3 h. To quench the reaction, triethylamine (0.1 mL) was added to the mixture at -60 °C, and the mixture was concentrated under reduced pressure at room temperature. The residue was purified by the silica gel column chromatography (eluent: n-hexane/EtOAc = 3/1 to 1/1) to give the desired product 8. The enantiomeric purity was determined by chiral HPLC analysis.

Determination of absolute stereochemistry of 8e:
To a solution of 8e (76.0 mg, 0.16 mmol, 97% ee) in diethyl ether (1.6 mL) was added methanol (13 µL, 0.32 mmol) followed by lithium borohydride (6.9 mg, 0.32 mmol) under nitrogen atmosphere at -78 °C. The mixture was stirred at 0 °C for 1 h. Saturated NH 4 Cl aqueous solution (2 mL) was then added to the mixture. The mixture was extracted with diethyl ether (5 mL × 2), and the combined organic layer was dried over Na 2 SO 4 . The organic phase was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane:EtOAc = 2:1 to 1:1), to give the desired product S30 in 83% yield (

Optimization of catalysts, protecting groups on substrates, and reaction temperature in the reaction of 2 with 7a.
Screening of the chiral catalysts in the probe reaction of 2 with 7a is summarized in Scheme S7.
Next, the protecting groups of the substrates 7 were optimized (Table S6). Here, we used unoptimized chiral bis(phosphoric acid) catalyst with n-Pr protection. As a result, for N-CO 2 Me-substrates, CO 2 Bn (Cbz) (entry 4) was much better than CO 2 Et (entry 1), CO 2 i-Pr (entry 2), and CO 2 t-Bu (Boc) (entry 3). Moreover, for Cbz-substrates, N-CO 2 Me (entry 4) was much better than N-Cbz (entry 5) and N-Boc (entry 6). Cbz N-Boc 83 0 Next, the ester moiety of the catalysts was optimized in a probe reaction of 2 with 7a (Table S7).
Without protection, the enantioselectivity of 8a was low (entry 1). In contrast, either catalyst with Me (entry 2), n-Pr (entry 3), or i-Pr (entry 4) protection was effective, and 8a was obtained in high yields with high enantioselectivities (92-95% ee). In particular, the catalyst with the i-Pr moiety (i.e., (R)-10c, entry 4) slightly more effective (95% ee) than the others. Next, the reaction temperature was examined in an unoptimized probe reaction (Table S8). At -78 °C, the reaction proceeded sluggishly, and the product was obtained in 79% yield with 70% ee (entry 1). At -40 °C, the reaction proceeded very smoothly, although the enantioselectivity was slightly reduced (64% ee) (entry 3). In contrast, at -60 °C, the reaction proceeded smoothly, and the product was obtained in 78% yield with 72% ee (entry 2). Based on these results, we set the temperature at -60 °C.

Preparation of (R)-S32 and the control experiments.
To a solution of (R)-10c (8.1 mg, 0.010 mmol) in dichloromethane (0.2 mL), one drop of N,N-dimethylformamide was added at room temperature. Then oxalyl chloride (3.0 µL, 0.035 mmol) was added at room temperature, and the mixture was warmed to 40 °C. The mixture was stirred at 40 °C for 5 min. Volatiles were removed in vacuo under heat conditions (ca. 40-50 °C).
The obtained (R)-S31 was used in the next step without further purification. (R)-S31 was dissolved in methanol (2 mL) and the solution was stirred at room temperature for 4 h. Excess mthanol was then removed in vacuo. The obtained product was dissolved in toluene (2 mL), and the volatiles were thoroughly removed under reduced pressure to give (R)-S32 as light brown solid.
The enantiomeric purity was determined by chiral HPLC analysis (95% ee).   (2.187 g, 4.61 mmol, 95% ee) in ethanol (15 mL) was added sodium borohydride (0.698 g, 18.4 mmol). The mixture was stirred at room temperature for 5 h, and concentrated under reduced pressure. The resultant residue was dissolved in dichloromethane (30 mL). Saturated NH 4 Cl aqueous solution (30 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3), and the combined organic layer was dried over Na 2 SO 4 . The organic phase was concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: n-hexane:EtOAc = 2:1 to 1:1) to give the desired product 20 (1.302 g, 84% yield, 95% ee).

Theoretical study on the E/Z-geometry of substrates 1b and 7a.
With regard to Eqs. 2 and 3 in the main text, we considered the E/Z-geometry of the substrates.
According to the literature, 1b would have an E-geometry, 6 whereas 7a would have a Z-geometry. 27 Indeed, a preliminary theoretical study was preliminary performed by a molecular mechanics method (MM2, Chem3D for Windows) (Fig. S12). As a result, (E)-1b was more stable than (Z)-1b by 8.12 kcal/mol (Fig. S12a). On the other hand, (Z)-7a was more stable than (E)-7a by 2.97 kcal/mol (Fig. S12b). Moreover, 1 H and 13 C NMR analyses of either 1b or 7a showed a single geometric isomer in CDCl 3 at room temperature, and thus the observed geometry (i.e., (E)-1b and (Z)-7a) should be quite stable.

Fig. S12
Theoretical study for the E/Z-geometry of substrates 1b and 7a.

CO 2 Et
N BnO 2 C i-Pr 3 Si

Possible transition states for the reactions.
Fig. S13a shows a possible transition state with the use of (R)-5b/1b/2. The imino nitrogen atom of 1b might coordinate to the C 2 -symmetric chiral Brønsted acid center of (R)-5b. Under these conditions, the sterically hindered i-Pr 3 Si moiety of 1b might be far from the 3,5-(o-Tol)C 6 H 3 moiety and turned outward to avoid steric constraints. Nucleophile 2 would then selectively attack the activated 1b from the si-face. As a result, enantioenriched (S)-3b might be provided (up to 91% ee). The steric effect of the silyl moiety might play an important role in the orientation of the substrates, and the sterically more hindered silyl moiety could induce high enantioselectivity: Ph (76% ee) < Ph 3 Si (79% ee) < t-BuMe 2 Si (82% ee) < t-BuPh 2 Si (88% ee) < i-Pr 3 Si (91% ee) (see Table S5). Fig. S13b shows a possible transition state with the use of (R)-10c/7a/2. The imino nitrogen atom of 7a might coordinate to the C 1 -symmetric chiral Brønsted acid center of (R)-10c. Under these conditions, the sterically hindered phenyl moiety of 7a might avoid steric constraints from the outstandingly bulky 2,4,6-Cy 3 C 6 H 2 moiety of catalyst (R)-10c. Nucleophile 2 would then selectively attack the activated 7a from the re-face. As a result, enantioenriched (R)-8a might be provided (up to 95% ee).