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Practical Enantioselective Reduction of Ketones Using Oxazaborolidine Catalysts Generated In Situ from Chiral Lactam Alcohols

Oxazaborolidine catalyst (CBS catalyst) has been extensively used for catalytic borane reduction with a predictable absolute stereochemistry and high enantioselectivity. However, the use of isolated CBS catalyst sometimes has the drawback of low reproducibility due to the aging of the CBS catalyst during storage. Therefore, we investigated a more reliable and practical method for the reduction of a variety of ketones including challenging substrates, primary aliphatic ketones, α,β-enones, and trifluoromethyl ketones. This review surveys the developments in borane reduction using oxazaborolidine catalysts generated in situ from chiral lactam alcohols and borane.

Introduction
Asymmetric reduction of prochiral ketones is one of the most important methods for the synthesis of chiral secondary alcohols and constitutes a valuable step in the synthesis of a variety of natural products and several medicinally important compounds. The oxazaborolidine-catalyzed asymmetric borane reduction of prochiral ketones (CBS reduction) using chiral amino alcohols [1][2][3][4] has been extensively investigated, since the stoichiometric reductions were reported by Itsuno et al. [5][6][7] and the catalytic versions were reported by Corey et al. [8]. The chiral amino alcohol, (S)-α,α-diphenyl-2-pyrrolidinemethnol (1) derived from (S)-proline has been widely accepted as superior one that permits efficient synthesis of chiral secondary alcohols with predictable absolute stereochemistries ( Figure 1). However, it has been described that the preparation of oxazaborolidine 1a requires heating at reflux with excess BH 3 in tetrahydrofuran (THF) [4]. On the other hand, Quallich et al. reported that the reaction of 1 with excess borane-dimethyl sulfide complex (BH 3 -Me 2 S) formed the oxazaborolidine 1a in THF at room temperature for 8-10 h (Scheme 1) [9]. Later, Yanagi et al. also reported that the catalyst 1a was generated from 1 and BH 3 -Me 2 S in THF, ether, and hexane at room temperature for 1 h [10]. Although the B-Me oxazaborolidine 1b formed by the reaction of 1 with methylboronic acid has been developed as an air-and moisture-stable catalyst that catalyzes the borane reduction of ketones with an excellent enantioselectivity [11], there is the requirement of complete removal of water to avoid undesired effects [12]. As part of our studies in asymmetric synthesis, we have investigated a more convenient and practical method for the reduction of a variety of ketones. This review surveys the developments in borane reduction using in situ generated oxazaborolidine catalysts from chiral lactam alcohols and borane over the last fifteen years. Furthermore, modifications of the method are described for the borane reduction of challenging substrates, i.e., primary aliphatic ketones, α,β-enones and trifluoromethyl ketones. are described for the borane reduction of challenging substrates, i.e., primary aliphatic ketones, α,β-enones and trifluoromethyl ketones.

Oxazaborolidine Catalyst Generated In Situ from a Chiral Lactam Alcohol and Borane
To overcome certain drawbacks, such as difficulties in handling and the reproducibility of the isolated oxazaborolidine catalysts, an alternative method was needed. We considered that the chiral lactam alcohol 2 [13], (S)-5-(diphenylhydroxymethyl)pyrrolidin-2-one, could be rapidly reduced with borane to the corresponding imine, which would be further reduced by the neighboring alkoxyborane to form the oxazaborolidine 1a (Scheme 2). This was inferred from the report that the racemic amino alcohol 1 could be prepared from the racemic lactam alcohol 2 through its reduction with borane [10]. Therefore, we conducted 11 B NMR analysis of the in situ generated oxazaborolidine catalyst as shown in Figure 2. The 11 B NMR (CDCl3) spectrum indicated the presence of the oxazaborolidine complex with borane (+17.7 ppm and −13.2 ppm) and free oxazaborolidine (+27.2 ppm) [14]. These chemical shifts were mostly consistent with those of the oxazaborolidine 1a generated in situ from (S)-diphenylpyrrolidinemethanol and borane [10]    are described for the borane reduction of challenging substrates, i.e., primary aliphatic ketones, α,β-enones and trifluoromethyl ketones.

Oxazaborolidine Catalyst Generated In Situ from a Chiral Lactam Alcohol and Borane
To overcome certain drawbacks, such as difficulties in handling and the reproducibility of the isolated oxazaborolidine catalysts, an alternative method was needed. We considered that the chiral lactam alcohol 2 [13], (S)-5-(diphenylhydroxymethyl)pyrrolidin-2-one, could be rapidly reduced with borane to the corresponding imine, which would be further reduced by the neighboring alkoxyborane to form the oxazaborolidine 1a (Scheme 2). This was inferred from the report that the racemic amino alcohol 1 could be prepared from the racemic lactam alcohol 2 through its reduction with borane [10]. Therefore, we conducted 11 B NMR analysis of the in situ generated oxazaborolidine catalyst as shown in Figure 2. The 11 B NMR (CDCl3) spectrum indicated the presence of the oxazaborolidine complex with borane (+17.7 ppm and −13.2 ppm) and free oxazaborolidine (+27.2 ppm) [14]. These chemical shifts were mostly consistent with those of the oxazaborolidine 1a generated in situ from (S)-diphenylpyrrolidinemethanol and borane [10]

Oxazaborolidine Catalyst Generated In Situ from a Chiral Lactam Alcohol and Borane
To overcome certain drawbacks, such as difficulties in handling and the reproducibility of the isolated oxazaborolidine catalysts, an alternative method was needed. We considered that the chiral lactam alcohol 2 [13], (S)-5-(diphenylhydroxymethyl)pyrrolidin-2-one, could be rapidly reduced with borane to the corresponding imine, which would be further reduced by the neighboring alkoxyborane to form the oxazaborolidine 1a (Scheme 2). This was inferred from the report that the racemic amino alcohol 1 could be prepared from the racemic lactam alcohol 2 through its reduction with borane [10].

Oxazaborolidine Catalyst Generated In Situ from a Chiral Lactam Alcohol and Borane
To overcome certain drawbacks, such as difficulties in handling and the reproducibility of the isolated oxazaborolidine catalysts, an alternative method was needed. We considered that the chiral lactam alcohol 2 [13], (S)-5-(diphenylhydroxymethyl)pyrrolidin-2-one, could be rapidly reduced with borane to the corresponding imine, which would be further reduced by the neighboring alkoxyborane to form the oxazaborolidine 1a (Scheme 2). This was inferred from the report that the racemic amino alcohol 1 could be prepared from the racemic lactam alcohol 2 through its reduction with borane [10]. Therefore, we conducted 11 B NMR analysis of the in situ generated oxazaborolidine catalyst as shown in Figure 2. The 11 B NMR (CDCl3) spectrum indicated the presence of the oxazaborolidine complex with borane (+17.7 ppm and −13.2 ppm) and free oxazaborolidine (+27.2 ppm) [14]. These chemical shifts were mostly consistent with those of the oxazaborolidine 1a generated in situ from (S)-diphenylpyrrolidinemethanol and borane [10]   Therefore, we conducted 11 B NMR analysis of the in situ generated oxazaborolidine catalyst as shown in Figure 2. The 11 B NMR (CDCl 3 ) spectrum indicated the presence of the oxazaborolidine complex with borane (+17.7 ppm and −13.2 ppm) and free oxazaborolidine (+27.2 ppm) [14]. These chemical shifts were mostly consistent with those of the oxazaborolidine 1a generated in situ from (S)-diphenylpyrrolidinemethanol and borane [10] under the same conditions.

Oxazaborolidine Catalyst Generated In Situ from a Chiral Lactam Alcohol and Borane
To overcome certain drawbacks, such as difficulties in handling and the reproducibility of the isolated oxazaborolidine catalysts, an alternative method was needed. We considered that the chiral lactam alcohol 2 [13], (S)-5-(diphenylhydroxymethyl)pyrrolidin-2-one, could be rapidly reduced with borane to the corresponding imine, which would be further reduced by the neighboring alkoxyborane to form the oxazaborolidine 1a (Scheme 2). This was inferred from the report that the racemic amino alcohol 1 could be prepared from the racemic lactam alcohol 2 through its reduction with borane [10]. Therefore, we conducted 11 B NMR analysis of the in situ generated oxazaborolidine catalyst as shown in Figure 2. The 11 B NMR (CDCl3) spectrum indicated the presence of the oxazaborolidine complex with borane (+17.7 ppm and −13.2 ppm) and free oxazaborolidine (+27.2 ppm) [14]. These chemical shifts were mostly consistent with those of the oxazaborolidine 1a generated in situ from (S)-diphenylpyrrolidinemethanol and borane [10]    As a result, we expected that the oxazaborolidine 1a generated in situ from 2 and borane should possibly catalyze the reduction of prochiral ketones with high enantioselectivities.

Asymmetric Reduction of Ketones
The lactam alcohol 2 was readily prepared by the reaction of phenylmagnesium bromide with methyl (S)-pyroglutamate as reported previously [13]. The reduction of the chiral lactam alcohol 2 (10 mol%) with 1 equivalent of BH 3 -THF smoothly proceeded at room temperature within 5 min. We found that the resulting oxazaborolidine intermediate catalyzed the borane reduction of various ketones, affording chiral secondary alcohols in good yields and enantiomeric excess (ee). The results are summarized in Scheme 3 [15].
As a result, we expected that the oxazaborolidine 1a generated in situ from 2 and borane should possibly catalyze the reduction of prochiral ketones with high enantioselectivities.

Asymmetric Reduction of Ketones
The lactam alcohol 2 was readily prepared by the reaction of phenylmagnesium bromide with methyl (S)-pyroglutamate as reported previously [13]. The reduction of the chiral lactam alcohol 2 (10 mol%) with 1 equivalent of BH3-THF smoothly proceeded at room temperature within 5 min. We found that the resulting oxazaborolidine intermediate catalyzed the borane reduction of various ketones, affording chiral secondary alcohols in good yields and enantiomeric excess (ee). The results are summarized in Scheme 3 [15].  The reduction of aryl methyl, ethyl, and chloromethyl ketone with borane and 10 mol% of 2 afforded the corresponding (R)-secondary alcohols, except for (S)-2-chloro-1-phenylethanol, with excellent enantioselectivities (91-98% ee). α-Tetralone, a cyclic aryl ketone, was reduced with good enantioselectivity (85% ee). The reduction of alkyl methyl ketones having a tertiary, secondary, and primary alkyl group proceeded with good to moderate enantioselectivities (89% ee, 81% ee, and 69% ee, respectively). Thus, the yields and enantioselectivities of the reduction using the lactam alcohol 2 and borane were comparable to those of the isolated catalyst 1a. Moreover, 1 could be obtained in good yield by extraction from aqueous acidic solution after quenching, suggesting that the lactam alcohol 2 was reduced by borane to actually generate the catalyst 1a in situ at room temperature in a short time.

Asymmetric Reduction of Aliphatic Ketones
Although the reduction of most aromatic ketones proceeded with excellent enantioselectivities, those of aliphatic ketones, in particular primary aliphatic ketones, usually afforded moderate enantioselectivities. For example, the enantioselectivity for the reduction of benzylacetone using 1a generated in situ from the chiral lactam alcohol 2 and borane was only 69% ee (that of Me-CBS 1b was 64% ee under the same reaction condition). Accordingly, we decided to modify the catalytic borane reduction using chiral lactam alcohol 2 to improve the enantioselectivity of the reduction of aliphatic ketones which are challenging substrates [16].
Shioiri et al. reported that trimethyl borate improved the reactivity and enantioselectivity of CBS reduction through the B-OMe oxazaborolidine 1d [17]. Therefore, we expected that the electronic effects of the boron substituent of the oxazaborolidine should enhance the reactivity and Scheme 3. Asymmetric reduction of ketones using chiral lactam alcohol 2. All reactions were carried out with 10 mol% of 2 and 1.0 equiv of BH 3 in THF at room temperature.
The reduction of aryl methyl, ethyl, and chloromethyl ketone with borane and 10 mol% of 2 afforded the corresponding (R)-secondary alcohols, except for (S)-2-chloro-1-phenylethanol, with excellent enantioselectivities (91-98% ee). α-Tetralone, a cyclic aryl ketone, was reduced with good enantioselectivity (85% ee). The reduction of alkyl methyl ketones having a tertiary, secondary, and primary alkyl group proceeded with good to moderate enantioselectivities (89% ee, 81% ee, and 69% ee, respectively). Thus, the yields and enantioselectivities of the reduction using the lactam alcohol 2 and borane were comparable to those of the isolated catalyst 1a. Moreover, 1 could be obtained in good yield by extraction from aqueous acidic solution after quenching, suggesting that the lactam alcohol 2 was reduced by borane to actually generate the catalyst 1a in situ at room temperature in a short time.

Asymmetric Reduction of Aliphatic Ketones
Although the reduction of most aromatic ketones proceeded with excellent enantioselectivities, those of aliphatic ketones, in particular primary aliphatic ketones, usually afforded moderate enantioselectivities. For example, the enantioselectivity for the reduction of benzylacetone using 1a generated in situ from the chiral lactam alcohol 2 and borane was only 69% ee (that of Me-CBS 1b was 64% ee under the same reaction condition). Accordingly, we decided to modify the catalytic borane reduction using chiral lactam alcohol 2 to improve the enantioselectivity of the reduction of aliphatic ketones which are challenging substrates [16].
Shioiri et al. reported that trimethyl borate improved the reactivity and enantioselectivity of CBS reduction through the B-OMe oxazaborolidine 1d [17]. Therefore, we expected that the electronic effects of the boron substituent of the oxazaborolidine should enhance the reactivity and enantioselectivity. First, BH 3 -THF solution was added dropwise to various alcohols in THF and stirred for 20 min at room temperature. During this period, the generation of H 2 was observed. Then, the chiral lactam alcohol 2 (10 mol%) was added to the alkoxyborane solution and stirred further for 1 h (Figure 3). Slow addition of benzylacetone as an aliphatic ketone to the catalyst generated in situ for 1 h afforded a (R)-secondary alcohol in good yields (74-90%, Scheme 4). While addition of neither methanol nor 2-propanol improved ee (69% ee, without the alcohols), the addition of substituted phenols afforded equal to slightly higher enantioselectivities (69-73% ee). We found a nonlinear dependence of enantioselectivity on the pK a of these phenols [18]. The most acidic p-(trifluoromethyl)phenol did not provide superior results (70% ee) and p-iodophenol provided the highest result (73% ee). These results suggest that p-iodophenoxy oxazaborolidine 1e has appropriate properties to increase the reactivity and enantioselectivity, though the reaction mechanism is very complicated due to possible involvement of several intermediate borane species. When p-iodophenol was added to the in situ generated 1a, the enantioselectivity decreased from 73% ee to 67% ee. This result indicated that the reduction of 2 with p-iodophenoxyborane should generate B-OAr oxazaborolidine catalyst 1e, though the detection of 1e by 11 B NMR analysis has not been successful, possibly due to its instability. enantioselectivity. First, BH3-THF solution was added dropwise to various alcohols in THF and stirred for 20 min at room temperature. During this period, the generation of H2 was observed. Then, the chiral lactam alcohol 2 (10 mol%) was added to the alkoxyborane solution and stirred further for 1 h ( Figure 3). Slow addition of benzylacetone as an aliphatic ketone to the catalyst generated in situ for 1 h afforded a (R)-secondary alcohol in good yields (74-90%, Scheme 4). While addition of neither methanol nor 2-propanol improved ee (69% ee, without the alcohols), the addition of substituted phenols afforded equal to slightly higher enantioselectivities (69-73% ee). We found a nonlinear dependence of enantioselectivity on the pKa of these phenols [18]. The most acidic p-(trifluoromethyl)phenol did not provide superior results (70% ee) and p-iodophenol provided the highest result (73% ee). These results suggest that p-iodophenoxy oxazaborolidine 1e has appropriate properties to increase the reactivity and enantioselectivity, though the reaction mechanism is very complicated due to possible involvement of several intermediate borane species. When p-iodophenol was added to the in situ generated 1a, the enantioselectivity decreased from 73% ee to 67% ee. This result indicated that the reduction of 2 with p-iodophenoxyborane should generate B-OAr oxazaborolidine catalyst 1e, though the detection of 1e by 11 B NMR analysis has not been successful, possibly due to its instability.  The screening of new chiral lactam alcohols with the 4-substituted or 3,5-disubstituted phenyl of the carbinol center revealed that the use of 3 with 3,5-dimethylphenyl improved the enantioselectivity from 73 to 79% ee. A nonlinear temperature effect on the enantioselectivity was also observed (Scheme 5). When the reaction temperature decreased from 20 °C to −20 °C, the enantioselectivity gradually increased up to 83% ee, and then dropped to 75% ee at −40 °C. This temperature effect contrasts with the reported result that general CBS reduction at lower enantioselectivity. First, BH3-THF solution was added dropwise to various alcohols in THF and stirred for 20 min at room temperature. During this period, the generation of H2 was observed. Then, the chiral lactam alcohol 2 (10 mol%) was added to the alkoxyborane solution and stirred further for 1 h ( Figure 3). Slow addition of benzylacetone as an aliphatic ketone to the catalyst generated in situ for 1 h afforded a (R)-secondary alcohol in good yields (74-90%, Scheme 4). While addition of neither methanol nor 2-propanol improved ee (69% ee, without the alcohols), the addition of substituted phenols afforded equal to slightly higher enantioselectivities (69-73% ee). We found a nonlinear dependence of enantioselectivity on the pKa of these phenols [18]. The most acidic p-(trifluoromethyl)phenol did not provide superior results (70% ee) and p-iodophenol provided the highest result (73% ee). These results suggest that p-iodophenoxy oxazaborolidine 1e has appropriate properties to increase the reactivity and enantioselectivity, though the reaction mechanism is very complicated due to possible involvement of several intermediate borane species. When p-iodophenol was added to the in situ generated 1a, the enantioselectivity decreased from 73% ee to 67% ee. This result indicated that the reduction of 2 with p-iodophenoxyborane should generate B-OAr oxazaborolidine catalyst 1e, though the detection of 1e by 11 B NMR analysis has not been successful, possibly due to its instability. The screening of new chiral lactam alcohols with the 4-substituted or 3,5-disubstituted phenyl of the carbinol center revealed that the use of 3 with 3,5-dimethylphenyl improved the enantioselectivity from 73 to 79% ee. A nonlinear temperature effect on the enantioselectivity was also observed (Scheme 5). When the reaction temperature decreased from 20 °C to −20 °C, the enantioselectivity gradually increased up to 83% ee, and then dropped to 75% ee at −40 °C. This temperature effect contrasts with the reported result that general CBS reduction at lower Scheme 4. Asymmetric reduction a of benzylacetone using chiral lactam alcohol 2. a All reactions were carried out with 10 mol% of 2 and 1.2 equiv of BH 3 and ROH in THF at room temperature. b pK a 9.99. c pK a 10.10. d pK a 9.17. e pK a 9.21. f pK a 8.68.
The screening of new chiral lactam alcohols with the 4-substituted or 3,5-disubstituted phenyl of the carbinol center revealed that the use of 3 with 3,5-dimethylphenyl improved the enantioselectivity from 73 to 79% ee. A nonlinear temperature effect on the enantioselectivity was also observed (Scheme 5). When the reaction temperature decreased from 20 • C to −20 • C, the enantioselectivity gradually increased up to 83% ee, and then dropped to 75% ee at −40 • C. This temperature effect contrasts with the reported result that general CBS reduction at lower temperature yielded lower enantioselectivities [19]. Therefore, we confirmed that the reduction with 3 (10 mol%) and BH 3 (1.2 equiv) at −20 • C resulted in a decrease in enantioselectivity, 35% ee, implying that a new oxazaborolidine catalyst 1e would generate from 3 and p-iodophenoxyborane. temperature yielded lower enantioselectivities [19]. Therefore, we confirmed that the reduction with 3 (10 mol%) and BH3 (1.2 equiv) at −20 °C resulted in a decrease in enantioselectivity, 35% ee, implying that a new oxazaborolidine catalyst 1e would generate from 3 and p-iodophenoxyborane. Under these optimized reaction conditions, the reduction of alkyl methyl ketones having a tertiary, secondary, and primary alkyl group with 3 and p-iodophenoxyborane proceeded with excellent to good enantioselectivities (98% ee, 81% ee, and 83% ee, respectively; Scheme 6). The reduction of cyclohexyl methyl ketone at room temperature proceeded with a better enantioselectivity (90% ee) contrary to that involving the other ketones, suggesting that the temperature effect is somewhat substrate-specific. OH OH Scheme 6. Asymmetric reduction of aliphatic ketones using the chiral lactam alcohol 3 and p-iodophenoxyborane. All reactions were carried out with 10 mol% of 3 and 1.2 equiv of BH3 and p-iodophenol in THF at −20 °C.

Asymmetric Reduction of α,β-Enones
Chiral allylic alcohols are important natural products [11] and the key intermediates for many stereospecific reactions, such as Claisen rearrangement [20], epoxidation [21], and SN2′ displacement with organometallic regents [22]. However, the reports concerning oxazaborolidine catalysis for the reduction of α,β-enones are very limited, probably due to the occurrence of a side reaction, i.e., hydroboration. For example, Corey et al. reported that the reduction of benzalacetone with Bu-CBS 1c (10-15 mol%) and 2 equiv. of catecholborane (CB) in toluene at −78 °C proceeded with excellent Scheme 5. Effect of temperature on enantioselectivity for the reduction of benzylacetone using 3 and p-iodophenoxyborane. All reactions were carried out with 10 mol% of 3 and 1.2 equiv of BH 3 and p-iodophenol in THF at room temperature.
Under these optimized reaction conditions, the reduction of alkyl methyl ketones having a tertiary, secondary, and primary alkyl group with 3 and p-iodophenoxyborane proceeded with excellent to good enantioselectivities (98% ee, 81% ee, and 83% ee, respectively; Scheme 6). The reduction of cyclohexyl methyl ketone at room temperature proceeded with a better enantioselectivity (90% ee) contrary to that involving the other ketones, suggesting that the temperature effect is somewhat substrate-specific. temperature yielded lower enantioselectivities [19]. Therefore, we confirmed that the reduction with 3 (10 mol%) and BH3 (1.2 equiv) at −20 °C resulted in a decrease in enantioselectivity, 35% ee, implying that a new oxazaborolidine catalyst 1e would generate from 3 and p-iodophenoxyborane.  Under these optimized reaction conditions, the reduction of alkyl methyl ketones having a tertiary, secondary, and primary alkyl group with 3 and p-iodophenoxyborane proceeded with excellent to good enantioselectivities (98% ee, 81% ee, and 83% ee, respectively; Scheme 6). The reduction of cyclohexyl methyl ketone at room temperature proceeded with a better enantioselectivity (90% ee) contrary to that involving the other ketones, suggesting that the temperature effect is somewhat substrate-specific. OH OH Scheme 6. Asymmetric reduction of aliphatic ketones using the chiral lactam alcohol 3 and p-iodophenoxyborane. All reactions were carried out with 10 mol% of 3 and 1.2 equiv of BH3 and p-iodophenol in THF at −20 °C.

Asymmetric Reduction of α,β-Enones
Chiral allylic alcohols are important natural products [11] and the key intermediates for many stereospecific reactions, such as Claisen rearrangement [20], epoxidation [21], and SN2′ displacement with organometallic regents [22]. However, the reports concerning oxazaborolidine catalysis for the reduction of α,β-enones are very limited, probably due to the occurrence of a side reaction, i.e., hydroboration. For example, Corey et al. reported that the reduction of benzalacetone with Bu-CBS 1c (10-15 mol%) and 2 equiv. of catecholborane (CB) in toluene at −78 °C proceeded with excellent Scheme 6. Asymmetric reduction of aliphatic ketones using the chiral lactam alcohol 3 and p-iodophenoxyborane. All reactions were carried out with 10 mol% of 3 and 1.2 equiv of BH 3 and p-iodophenol in THF at −20 • C.

Asymmetric Reduction of α,β-Enones
Chiral allylic alcohols are important natural products [11] and the key intermediates for many stereospecific reactions, such as Claisen rearrangement [20], epoxidation [21], and S N 2 displacement with organometallic regents [22]. However, the reports concerning oxazaborolidine catalysis for the reduction of α,β-enones are very limited, probably due to the occurrence of a side reaction, i.e., hydroboration. For example, Corey et al. reported that the reduction of benzalacetone with Bu-CBS 1c (10-15 mol%) and 2 equiv. of catecholborane (CB) in toluene at −78 • C proceeded with excellent enantioselectivity (92% ee) [23], as shown in Scheme 7. On the other hand, Bach et al. described that the reduction of benzalacetone using 4 and BH 3 -Me 2 S in THF at 0 • C provided a lower enantioselectivity (82% ee) [24]. Recently, Falck et al. also reported the enantioselective reduction of benzalacetone using CB and air-stable bifunctional thiourea-amine organocatalyst 5, instead of CBS oxazaborolidine catalyst, with a high enantioselectivity (90% ee) [25]. In this context, we investigated the enantioselective reduction of α,β-enones as challenging substrates using the oxazaborolidine generated in situ from the chiral lactam alcohol 3 to expand its scope and generality [26].
Molecules 2018, 23, x FOR PEER REVIEW 6 of 14 enantioselectivity (92% ee) [23], as shown in Scheme 7. On the other hand, Bach et al. described that the reduction of benzalacetone using 4 and BH3-Me2S in THF at 0 °C provided a lower enantioselectivity (82% ee) [24]. Recently, Falck et al. also reported the enantioselective reduction of benzalacetone using CB and air-stable bifunctional thiourea-amine organocatalyst 5, instead of CBS oxazaborolidine catalyst, with a high enantioselectivity (90% ee) [25]. In this context, we investigated the enantioselective reduction of α,β-enones as challenging substrates using the oxazaborolidine generated in situ from the chiral lactam alcohol 3 to expand its scope and generality [26]. We first examined the effect of the alcohol on the enantioselectivity of the reduction of benzalacetone as a substrate using the chiral lactam alcohol 3 (10 mol%) and BH3-THF at 0 °C because the reduction with 3 and BH3-THF afforded a complicated mixture as a result of the hydroboration side reaction. We found that the addition of p-iodophenol significantly increased the enantioselectivity compared to 2-propanol [27,28] and p-halogen substituted phenols as shown in Table 1. Then, we examined the solvent effect in the reduction with 3 and p-iodophenoxyborane. Toluene afforded a higher yield than THF and the polar solvents, dichloromethane (CH2Cl2) and chloroform (CHCl3), afforded somewhat lower enantioselectivities (56% ee and 66% ee).  We first examined the effect of the alcohol on the enantioselectivity of the reduction of benzalacetone as a substrate using the chiral lactam alcohol 3 (10 mol%) and BH 3 -THF at 0 • C because the reduction with 3 and BH 3 -THF afforded a complicated mixture as a result of the hydroboration side reaction. We found that the addition of p-iodophenol significantly increased the enantioselectivity compared to 2-propanol [27,28] and p-halogen substituted phenols as shown in Table 1. Then, we examined the solvent effect in the reduction with 3 and p-iodophenoxyborane. Toluene afforded a higher yield than THF and the polar solvents, dichloromethane (CH 2 Cl 2 ) and chloroform (CHCl 3 ), afforded somewhat lower enantioselectivities (56% ee and 66% ee). Table 1. Asymmetric reduction of α,β-enones using the chiral lactam alcohol 3 a .
Molecules 2018, 23, x FOR PEER REVIEW 6 of 14 enantioselectivity (92% ee) [23], as shown in Scheme 7. On the other hand, Bach et al. described that the reduction of benzalacetone using 4 and BH3-Me2S in THF at 0 °C provided a lower enantioselectivity (82% ee) [24]. Recently, Falck et al. also reported the enantioselective reduction of benzalacetone using CB and air-stable bifunctional thiourea-amine organocatalyst 5, instead of CBS oxazaborolidine catalyst, with a high enantioselectivity (90% ee) [25]. In this context, we investigated the enantioselective reduction of α,β-enones as challenging substrates using the oxazaborolidine generated in situ from the chiral lactam alcohol 3 to expand its scope and generality [26]. We first examined the effect of the alcohol on the enantioselectivity of the reduction of benzalacetone as a substrate using the chiral lactam alcohol 3 (10 mol%) and BH3-THF at 0 °C because the reduction with 3 and BH3-THF afforded a complicated mixture as a result of the hydroboration side reaction. We found that the addition of p-iodophenol significantly increased the enantioselectivity compared to 2-propanol [27,28] and p-halogen substituted phenols as shown in Table 1. Then, we examined the solvent effect in the reduction with 3 and p-iodophenoxyborane. Toluene afforded a higher yield than THF and the polar solvents, dichloromethane (CH2Cl2) and chloroform (CHCl3), afforded somewhat lower enantioselectivities (56% ee and 66% ee). Stone demonstrated that Ph-CBS catalyst is more sensitive to temperature change than Me-and Bu-CBS catalysts and indicated that CBS reduction may be optimized to obtain the highest selectivity possible for a given catalyst and ketone by adjusting the temperature [19]. Therefore, we examined the temperature effect on enantioselectivity for the reduction of benzalacetone using the in situ generated p-I-PhO-oxazaborolidine catalyst 1e.
When the reaction temperature is lowered from 0 • C to −60 • C, the enantioselectivity increased up to 84% ee at −40 • C, and then dropped to 63% ee at −60 • C (Table 2). Therefore, the optimal temperature in toluene was found to be −40 • C. The temperature effect might be attributed to the acceleration of the catalytic cycle as a result of the dissociation of the product D and the regeneration of the catalyst from the reaction intermediate C (Scheme 8). Interestingly, we observed that the enantioselectivity was susceptible to the balance between the borane equivalents and catalyst loading. When 8 mol% of the chiral lactam alcohol 3 and 1.0 equiv. of p-I-PhOBH 2 were used, the enantioselectivity increased up to 90% ee. Table 2. Effect of temperature, ligand loading, and borane equivalent on enantioselectivity for the reduction of benzalacetone using chiral lactam alcohol 3 and p-iodophenoxyborane a . Stone demonstrated that Ph-CBS catalyst is more sensitive to temperature change than Me-and Bu-CBS catalysts and indicated that CBS reduction may be optimized to obtain the highest selectivity possible for a given catalyst and ketone by adjusting the temperature [19]. Therefore, we examined the temperature effect on enantioselectivity for the reduction of benzalacetone using the in situ generated p-I-PhO-oxazaborolidine catalyst 1e.
When the reaction temperature is lowered from 0 °C to −60 °C, the enantioselectivity increased up to 84% ee at −40 °C, and then dropped to 63% ee at −60 °C (Table 2). Therefore, the optimal temperature in toluene was found to be −40 °C. The temperature effect might be attributed to the acceleration of the catalytic cycle as a result of the dissociation of the product D and the regeneration of the catalyst from the reaction intermediate C (Scheme 8). Interestingly, we observed that the enantioselectivity was susceptible to the balance between the borane equivalents and catalyst loading. When 8 mol% of the chiral lactam alcohol 3 and 1.0 equiv. of p-I-PhOBH2 were used, the enantioselectivity increased up to 90% ee. Table 2. Effect of temperature, ligand loading, and borane equivalent on enantioselectivity for the reduction of benzalacetone using chiral lactam alcohol 3 and p-iodophenoxyborane a . The absolute configuration of the resulting secondary alcohol was (R), which agreed with the reduction process catalyzed by Bu-CBS 1c [23]. The enantioselectivity was proposed to originate via a six-membered transition state B shown in Scheme 8 [4]. Therefore, this result can be explained by Stone demonstrated that Ph-CBS catalyst is more sensitive to temperature change than Me-and Bu-CBS catalysts and indicated that CBS reduction may be optimized to obtain the highest selectivity possible for a given catalyst and ketone by adjusting the temperature [19]. Therefore, we examined the temperature effect on enantioselectivity for the reduction of benzalacetone using the in situ generated p-I-PhO-oxazaborolidine catalyst 1e.

Temp. (°C) 3 (mol%) p-I-PhOBH2 (equiv) Yield (%) ee (%)
When the reaction temperature is lowered from 0 °C to −60 °C, the enantioselectivity increased up to 84% ee at −40 °C, and then dropped to 63% ee at −60 °C (Table 2). Therefore, the optimal temperature in toluene was found to be −40 °C. The temperature effect might be attributed to the acceleration of the catalytic cycle as a result of the dissociation of the product D and the regeneration of the catalyst from the reaction intermediate C (Scheme 8). Interestingly, we observed that the enantioselectivity was susceptible to the balance between the borane equivalents and catalyst loading. When 8 mol% of the chiral lactam alcohol 3 and 1.0 equiv. of p-I-PhOBH2 were used, the enantioselectivity increased up to 90% ee. Table 2. Effect of temperature, ligand loading, and borane equivalent on enantioselectivity for the reduction of benzalacetone using chiral lactam alcohol 3 and p-iodophenoxyborane a . The absolute configuration of the resulting secondary alcohol was (R), which agreed with the reduction process catalyzed by Bu-CBS 1c [23]. The enantioselectivity was proposed to originate via a six-membered transition state B shown in Scheme 8 [4]. Therefore, this result can be explained by The absolute configuration of the resulting secondary alcohol was (R), which agreed with the reduction process catalyzed by Bu-CBS 1c [23]. The enantioselectivity was proposed to originate via a six-membered transition state B shown in Scheme 8 [4]. Therefore, this result can be explained by a transition state model (Figure 4) in which the olefinic part behaves as the large group R L and the hydride of 4-I-PhOBH 2 would attack on the Si-face of the carbonyl carbon of benzalacetone to give the (R)-alcohol. Under the optimized conditions, we investigated the borane reduction of various α,β-enones to evaluate the scope and limitations of the substrate. As shown in Scheme 9, the reduction of p-chloro and p-methyl substituted benzalacetones proceeded with a slightly lower enantioselectivity than that of benzalacetone, regardless of their electronic properties. The bulkier 4-(1-naphtyl)-3-butene-2-one was reduced with 86% ee. The reduction of 6-phenyl-3-buten-2-one proceeded with a slightly lower enantioselectivity (83% ee) compared to that of benzalacetone, possibly due to the lack of conjugation with the benzene ring. Although the reduction of the cyclic enone, 1-acetylcyclohexene afforded a high enantioselectivity (85% ee), the reduction of the exocyclic enone, phenylmethylidenecyclohexanone, revealed a moderate enantioselectivity (76% ee). This result can be explained by the less stable s-cis conformation of the exocyclic enone, unlike the s-trans conformation of the cyclic enone and other enones of the transition state ( Figure 4).   Under the optimized conditions, we investigated the borane reduction of various α,β-enones to evaluate the scope and limitations of the substrate. As shown in Scheme 9, the reduction of p-chloro and p-methyl substituted benzalacetones proceeded with a slightly lower enantioselectivity than that of benzalacetone, regardless of their electronic properties. The bulkier 4-(1-naphtyl)-3-butene-2-one was reduced with 86% ee. The reduction of 6-phenyl-3-buten-2-one proceeded with a slightly lower enantioselectivity (83% ee) compared to that of benzalacetone, possibly due to the lack of conjugation with the benzene ring. Although the reduction of the cyclic enone, 1-acetylcyclohexene afforded a high enantioselectivity (85% ee), the reduction of the exocyclic enone, phenylmethylidenecyclohexanone, revealed a moderate enantioselectivity (76% ee). This result can be explained by the less stable s-cis conformation of the exocyclic enone, unlike the s-trans conformation of the cyclic enone and other enones of the transition state ( Figure 4). Under the optimized conditions, we investigated the borane reduction of various α,β-enones to evaluate the scope and limitations of the substrate. As shown in Scheme 9, the reduction of p-chloro and p-methyl substituted benzalacetones proceeded with a slightly lower enantioselectivity than that of benzalacetone, regardless of their electronic properties. The bulkier 4-(1-naphtyl)-3-butene-2-one was reduced with 86% ee. The reduction of 6-phenyl-3-buten-2-one proceeded with a slightly lower enantioselectivity (83% ee) compared to that of benzalacetone, possibly due to the lack of conjugation with the benzene ring. Although the reduction of the cyclic enone, 1-acetylcyclohexene afforded a high enantioselectivity (85% ee), the reduction of the exocyclic enone, phenylmethylidenecyclohexanone, revealed a moderate enantioselectivity (76% ee). This result can be explained by the less stable s-cis conformation of the exocyclic enone, unlike the s-trans conformation of the cyclic enone and other enones of the transition state ( Figure 4).

Scheme 9.
Asymmetric reduction of α,β-enones using 3 and p-iodophenoxyborane. All reactions were carried out with 10 mol% of 3 and 1.2 equiv of BH3 and p-iodophenol in THF at −40 °C.

Scheme 9.
Asymmetric reduction of α,β-enones using 3 and p-iodophenoxyborane. All reactions were carried out with 10 mol% of 3 and 1.2 equiv of BH 3 and p-iodophenol in THF at −40 • C.

Asymmetric Reduction of Trifluoromethyl Ketones
Fluorine-containing chiral alcohols have recently been studied as potentially good precursors for preparing ferroelectric liquid crystals [29]. However, because of their high reactivity, the oxazaborolidinecatalyzed asymmetric borane reduction of trifluoromethyl ketones usually affords the corresponding chiral secondary alcohols with a poor enantioselectivity [4], except for the reduction of the trifluoromethyl ketones with Bu-CBS 1c and CB [30,31]. This low enantioselectivity can be explained by the low coordinating ability of the carbonyl oxygen to the oxazaborolidine catalyst and the noncatalytic reduction with borane. It was also reported that the oxazaborolidine 6 derived from L-threonine and CB at −90 • C afforded high enantioselectivities [32]. On the other hand, other methods using the catalyst prepared from (S)-diphenylpyrrolidinemethanol with 9-borabicyclo[3.3.1]nonane (9-BBN) 7 [33], spiroborate ester 8 [34], and electronically tuned-CBS catalyst 1f with high Lewis acidity [35] have been reported with good to high enantioselectivities and, interestingly, stereochemistry opposite to that of 1c (Scheme 10). Therefore, we set out to investigate the catalytic asymmetric reduction of trifluoromethyl ketones using the simple oxazaborolidine 1a generated in situ from the chiral lactam alcohol 2 and borane [14,36] to clarify its scope and enantioselection.

Asymmetric Reduction of Trifluoromethyl Ketones
Fluorine-containing chiral alcohols have recently been studied as potentially good precursors for preparing ferroelectric liquid crystals [29]. However, because of their high reactivity, the oxazaborolidine-catalyzed asymmetric borane reduction of trifluoromethyl ketones usually affords the corresponding chiral secondary alcohols with a poor enantioselectivity [4], except for the reduction of the trifluoromethyl ketones with Bu-CBS 1c and CB [30,31]. This low enantioselectivity can be explained by the low coordinating ability of the carbonyl oxygen to the oxazaborolidine catalyst and the noncatalytic reduction with borane. It was also reported that the oxazaborolidine 6 derived from L-threonine and CB at −90 °C afforded high enantioselectivities [32]. On the other hand, other methods using the catalyst prepared from (S)-diphenylpyrrolidinemethanol with 9-borabicyclo[3.3.1]nonane (9-BBN) 7 [33], spiroborate ester 8 [34], and electronically tuned-CBS catalyst 1f with high Lewis acidity [35] have been reported with good to high enantioselectivities and, interestingly, stereochemistry opposite to that of 1c (Scheme 10). Therefore, we set out to investigate the catalytic asymmetric reduction of trifluoromethyl ketones using the simple oxazaborolidine 1a generated in situ from the chiral lactam alcohol 2 and borane [14,36]   We first examined the effect of borane reagents on enantioselectivity for the reduction of trifluoroacetophenone as shown in Table 3. Various borane reagents, BH3-THF, BH3-Me2S, CB, and p-I-PhOBH2 were used at room temperature. Although the reduction with BH3-Me2S or CB resulted in small enantioselectivities and the use of p-I-PhOBH2, which was effective for the reduction of aliphatic ketones [17], did not improve the enantioselectivity, the use of BH3-THF was found to be optimal as a reducing borane reagent for our method. Further study of the solvent revealed that the We first examined the effect of borane reagents on enantioselectivity for the reduction of trifluoroacetophenone as shown in Table 3. Various borane reagents, BH 3 -THF, BH 3 -Me 2 S, CB, and p-I-PhOBH 2 were used at room temperature. Although the reduction with BH 3 -Me 2 S or CB resulted in small enantioselectivities and the use of p-I-PhOBH 2, which was effective for the reduction of aliphatic ketones [17], did not improve the enantioselectivity, the use of BH 3 -THF was found to be optimal as a reducing borane reagent for our method. Further study of the solvent revealed that the polar solvent CHCl 3 afforded a significantly higher enantioselectivity (up to 80% ee) for the reduction with 2 and BH 3 -THF. However, we observed variable enantioselectivities depending on the storage period of BH 3 -THF. To our surprise, when a new commercially available BH 3 -THF (stabilized with ca. 0.005 M NaBH 4 ) was employed, only lower enantioselectivities (55% ee) were obtained. These results imply that a properly degraded BH 3 -THF is superior to the one containing NaBH 4 -stabilizer possibly due to the butoxyborane species produced by the reduction of THF with BH 3 -THF during storage, as reported by Nettles et al. [37]. They also described that the addition of a Lewis acid deactivated the NaBH 4 stabilizer in BH 3 -THF and that the BF 3 -THF complex (3-8 mol%) proved to be the best with a high enantioselectivity for the reduction of acetophenone among the examined Lewis acids. Fu et al. simultaneously reported that the chemo-and enantioselectivities dramatically increased when using an acid (5 mol% of BF 3 -OEt 2 or p-toluenesulfonic acid) as a scavenger of the NaBH 4 stabilizer in BH 3 -THF for the reduction of a ketone having the chiral 4-phenyl-2-oxazolidinone auxiliary [38]. Therefore, we expected that addition of BF 3 could enhance the enantioselectivity for the reduction of trifluoroacetophenone with the oxazaborolidine 1a. The reduction with 2 (10 mol%) and BH 3 -THF (0.8 equiv.) in the presence of BF 3 (8 mol%) provided the (S)-alcohol in 85% yield, with a higher enantioselectivity (60% ee) compared to that without BF 3 , implying that the BF 3 remaining after scavenging the NaBH 4 stabilizer might enhance the enantioselectivity. Accordingly, we carefully examined the effect of BF 3 loading on the enantioselectivity, which was not described in the papers mentioned above ( [37,38]). The enantioselectivity increased depending on the BF 3 loading and reached 80% ee at 160 mol%, which was found to be the best loading after screening for the optimal loading. To clarify the effect of its addition, 8 and 160 mol% of BF 3 were added to the reduction process using the pure BH 3 generated in situ from tetra-n-butylammonium borohydride (TBAB) and methyl iodide (MeI) [39], thus producing the (S)-alcohol in high yield and with high enantioselectivities. These results suggested that excess BF 3 -THF not only deactivated NaBH 4 stabilizer, but also actually improved the enantioselectivity. Table 3. Asymmetric reduction of 2,2,2-trifluoroacetophenone using lactam alcohol 2 a .
Molecules 2018, 23, x FOR PEER REVIEW 10 of 14 polar solvent CHCl3 afforded a significantly higher enantioselectivity (up to 80% ee) for the reduction with 2 and BH3-THF. However, we observed variable enantioselectivities depending on the storage period of BH3-THF. To our surprise, when a new commercially available BH3-THF (stabilized with ca. 0.005 M NaBH4) was employed, only lower enantioselectivities (55% ee) were obtained. These results imply that a properly degraded BH3-THF is superior to the one containing NaBH4-stabilizer possibly due to the butoxyborane species produced by the reduction of THF with BH3-THF during storage, as reported by Nettles et al. [37]. They also described that the addition of a Lewis acid deactivated the NaBH4 stabilizer in BH3-THF and that the BF3-THF complex (3-8 mol%) proved to be the best with a high enantioselectivity for the reduction of acetophenone among the examined Lewis acids. Fu et al. simultaneously reported that the chemo-and enantioselectivities dramatically increased when using an acid (5 mol% of BF3-OEt2 or p-toluenesulfonic acid) as a scavenger of the NaBH4 stabilizer in BH3-THF for the reduction of a ketone having the chiral 4-phenyl-2-oxazolidinone auxiliary [38]. Therefore, we expected that addition of BF3 could enhance the enantioselectivity for the reduction of trifluoroacetophenone with the oxazaborolidine 1a. The reduction with 2 (10 mol%) and BH3-THF (0.8 equiv.) in the presence of BF3 (8 mol%) provided the (S)-alcohol in 85% yield, with a higher enantioselectivity (60% ee) compared to that without BF3, implying that the BF3 remaining after scavenging the NaBH4 stabilizer might enhance the enantioselectivity. Accordingly, we carefully examined the effect of BF3 loading on the enantioselectivity, which was not described in the papers mentioned above ( [37,38]). The enantioselectivity increased depending on the BF3 loading and reached 80% ee at 160 mol%, which was found to be the best loading after screening for the optimal loading. To clarify the effect of its addition, 8 and 160 mol% of BF3 were added to the reduction process using the pure BH3 generated in situ from tetra-n-butylammonium borohydride (TBAB) and methyl iodide (MeI) [39], thus producing the (S)-alcohol in high yield and with high enantioselectivities. These results suggested that excess BF3-THF not only deactivated NaBH4 stabilizer, but also actually improved the enantioselectivity. The stereochemistry of the resulting secondary alcohol during the reduction with BH3-THF was the same (S)-configuration as that observed for the reductions catalyzed by 1f [35], 7 [33], and 8 [34], suggesting that the hydride attack on the Re-face of the carbonyl group of trifluoroacetophenone might occur via a typical transition state ( Figure 5A)  The stereochemistry of the resulting secondary alcohol during the reduction with BH 3 -THF was the same (S)-configuration as that observed for the reductions catalyzed by 1f [35], 7 [33], and 8 [34], suggesting that the hydride attack on the Re-face of the carbonyl group of trifluoroacetophenone might occur via a typical transition state ( Figure 5A) for general CBS reductions.   Figure 5B) for the reverse (R)-enantioselection occurring hydride attack on the Si-face of the carbonyl group during the reduction with Bu-CBS 1c and CB at −78 °C due to the electrostatic repulsion between the trifluoromethyl group and the lone pair of the carbonyl group. To clarify whether the addition of BF3 causes a change in the oxazaborolidine catalyst, we carried out 11 B NMR study of the in situ generated oxazaborolidine catalyst in the presence of BF3. The 11 B NMR analysis revealed that the major signals (+17.7 ppm and −13.2 ppm) of the oxazaborolidine complex with BH3-THF and free oxazaborolidine (−27.2 ppm) did not change upon the addition of BF3-THF to the catalyst solution. Thus, an interaction between the oxazaborolidine catalyst and BF3-THF was deemed to be negligible, if any. These results suggested that BF3 might not coordinate to the in situ generated catalyst, but rather coordinate to trifluoroacetophenone, in an anti-relationship to the trifluoromethyl group, thereby stabilizing the complex in the transition state ( Figure 5C).
Under the optimized reaction conditions, the reduction of aromatic trifluoromethyl ketones including the para-substituted biphenyl trifluoromethyl ketones proceeded with moderate to high enantioselectivities as shown in Scheme 11. The electron-donating methoxy and phenyl groups of the benzene ring increased the enantioselectivity to 86 and 90% ee, respectively. The reduction of the biphenyl trifluoromethyl ketone with the methoxy group afforded the (S)-alcohol in 90% yield with the enantioselectivity of 86% ee, which is similar to that obtained from the reduction with Bu-CBS 1c or the oxazaborolidine derived from L-threonine and CB at −90 °C, but the opposite (S)-configuration [33]. On the other hand, the biphenyl trifluoromethyl ketone with an electron-withdrawing bromo group was reduced with modest enantioselectivity (71% ee).    Figure 5B) for the reverse (R)-enantioselection occurring hydride attack on the Si-face of the carbonyl group during the reduction with Bu-CBS 1c and CB at −78 • C due to the electrostatic repulsion between the trifluoromethyl group and the lone pair of the carbonyl group. To clarify whether the addition of BF 3 causes a change in the oxazaborolidine catalyst, we carried out 11 B NMR study of the in situ generated oxazaborolidine catalyst in the presence of BF 3 . The 11 B NMR analysis revealed that the major signals (+17.7 ppm and −13.2 ppm) of the oxazaborolidine complex with BH 3 -THF and free oxazaborolidine (−27.2 ppm) did not change upon the addition of BF 3 -THF to the catalyst solution. Thus, an interaction between the oxazaborolidine catalyst and BF 3 -THF was deemed to be negligible, if any. These results suggested that BF 3 might not coordinate to the in situ generated catalyst, but rather coordinate to trifluoroacetophenone, in an anti-relationship to the trifluoromethyl group, thereby stabilizing the complex in the transition state ( Figure 5C).
Under the optimized reaction conditions, the reduction of aromatic trifluoromethyl ketones including the para-substituted biphenyl trifluoromethyl ketones proceeded with moderate to high enantioselectivities as shown in Scheme 11. The electron-donating methoxy and phenyl groups of the benzene ring increased the enantioselectivity to 86 and 90% ee, respectively. The reduction of the biphenyl trifluoromethyl ketone with the methoxy group afforded the (S)-alcohol in 90% yield with the enantioselectivity of 86% ee, which is similar to that obtained from the reduction with Bu-CBS 1c or the oxazaborolidine derived from L-threonine and CB at −90 • C, but the opposite (S)-configuration [33]. On the other hand, the biphenyl trifluoromethyl ketone with an electron-withdrawing bromo group was reduced with modest enantioselectivity (71% ee).   Figure 5B) for the reverse (R)-enantioselection occurring hydride attack on the Si-face of the carbonyl group during the reduction with Bu-CBS 1c and CB at −78 °C due to the electrostatic repulsion between the trifluoromethyl group and the lone pair of the carbonyl group. To clarify whether the addition of BF3 causes a change in the oxazaborolidine catalyst, we carried out 11 B NMR study of the in situ generated oxazaborolidine catalyst in the presence of BF3. The 11 B NMR analysis revealed that the major signals (+17.7 ppm and −13.2 ppm) of the oxazaborolidine complex with BH3-THF and free oxazaborolidine (−27.2 ppm) did not change upon the addition of BF3-THF to the catalyst solution. Thus, an interaction between the oxazaborolidine catalyst and BF3-THF was deemed to be negligible, if any. These results suggested that BF3 might not coordinate to the in situ generated catalyst, but rather coordinate to trifluoroacetophenone, in an anti-relationship to the trifluoromethyl group, thereby stabilizing the complex in the transition state ( Figure 5C).
Under the optimized reaction conditions, the reduction of aromatic trifluoromethyl ketones including the para-substituted biphenyl trifluoromethyl ketones proceeded with moderate to high enantioselectivities as shown in Scheme 11. The electron-donating methoxy and phenyl groups of the benzene ring increased the enantioselectivity to 86 and 90% ee, respectively. The reduction of the biphenyl trifluoromethyl ketone with the methoxy group afforded the (S)-alcohol in 90% yield with the enantioselectivity of 86% ee, which is similar to that obtained from the reduction with Bu-CBS 1c or the oxazaborolidine derived from L-threonine and CB at −90 °C, but the opposite (S)-configuration [33]. On the other hand, the biphenyl trifluoromethyl ketone with an electron-withdrawing bromo group was reduced with modest enantioselectivity (71% ee).  Scheme 11. Asymmetric reduction of various trifluoromethyl ketones using 2. All reactions were carried out with 10 mol% of 2, 160 mol% of BF 3 and 0.8 equiv of BH 3 in CHCl 3 at room temperature. a Temperature, 40 • C.

Conclusions
We have demonstrated that the oxazaborolidine catalysts generated in situ from the chiral lactam alcohol 2 and borane catalyzed the enantioselective reduction of aromatic ketones with high enantioselectivities. Furthermore, in the case of aliphatic ketones and α,β-enones, the use of p-iodophenoxyborane improved the enantioselectivities at low temperatures and, in the case of trifluoromethyl ketones, the addition of BF 3 enhanced the enantioselectivities at room temperature. These modified methods offer good reproducibility and render the catalytic borane reductions more practical because these catalysts can be easily generated in situ from stable chiral lactam alcohols and borane before use.
Author Contributions: This review article was conceived by Y.K., in consultation with R.C.Y.
Funding: This research was financially supported in part by Tosoh Co., Tokyo, Japan.


extfieldsofstudy: Chemistry Medicine

text:
Synthesis of Benzofuran-2-One Derivatives and Evaluation of Their Antioxidant Capacity by Comparing DPPH Assay and Cyclic Voltammetry

The present work aimed to synthesise promising antioxidant compounds as a valuable alternative to the currently expensive and easily degradable molecules that are employed as stabilizers in industrial preparation. Taking into account our experience concerning domino Friedel-Crafts/lactonization reactions, we successfully improved and extended the previously reported methodology toward the synthesis of 3,3-disubstituted-3H-benzofuran-2-one derivatives 9–20 starting from polyphenols 1–6 as substrates and either diethylketomalonate (7) or 3,3,3-trifluoromethyl pyruvate (8) as electrophilic counterpart. The antioxidant capacity of the most stable compounds (9–11 and 15–20) was evaluated by both DPPH assay and Cyclic Voltammetry analyses performed in alcoholic media (methanol) as well as in aprotic solvent (acetonitrile). By comparing the recorded experimental data, a remarkable activity can be attributed to few of the tested lactones.

General Information
Solvents and common reagents were purchased from a commercial source and used without further purification. All reactions were monitored by thin-layer chromatography (TLC) carried out on Merck F-254 silica glass plates and visualized with UV light or by 5% phosphomolibdic acid/ethanol test. Flash chromatography was performed on Sigma-Aldrich silica gel (60, particle size: 0.040-0.063 mm). 1 H-NMR and 13 C-NMR were recorded in CDCl3 (99.8% in deuterium) using a Varian Gemini 300 spectrometer (300 MHz, Varian inc., Palo Alto, CA, USA). All chemical shifts are expressed in parts per million (δ scale) and are referenced to the residual protons of the NMR solvent (CDCl3, δ 7.24 ppm). Coupling constant (J) was expressed in Hz. Infrared spectra (FT-IR) were obtained using a Bruker Vector 22 spectrometer (Bruker, Billerica, MA, USA); data are presented as the frequency of absorption (cm −1 ). High-resolution mass spectrometry (HRMS) spectra were recorded with Micromass Q-TOF micro mass spectrometer (Waters Corporations, Milford, MA, USA) and Micromass LCT (ESI, Waters Corporations, Milford, MA, USA) with Lock-Spray-Injector (Injection Loop-Modus in a HPLC system, Waters, Alliance 2695). UV-Vis measurements were performed with a Shimadzu-UV-2401PC spectrophotometer. Cyclic Voltammetry measurements were acquired on a AMEL552 electrochemical workstation. The standard three-electrode arrangement was employed. In all case, a Pt wire auxiliary electrode was used, the working electrode was a 3 mm diameter glassy carbon, and the solution was degassed with N2.
Melting points were determined on a Mel-Temp apparatus.).

General Procedure for the Lewis-acid-catalysed Friedel-Crafts/lactonization reaction
The alkylating agent (2.2 mmol) was added in one portion to a stirred solution of the appropriate phenol (2.0 mmol) in anhydrous CHCl3 (9 mL), and then TiCl4 (1 M in anhydrous CH2Cl2; 0.4 mL, 10 mol-%) was added.
The system was kept under an argon atmosphere. The clear reddish solution was stirred at the reported temperature until the substrate had been completely consumed (TLC monitoring). Afterwards, the reaction mixture was poured into cold water (18 mL), and the aqueous phase was extracted several times with EtOAc (4 x 20 mL). The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give the products as described below.

Characterization Data for benzofuran 9-11
Following the general procedure, the single product 9 was obtained as a white solid in 70% yield after purification by flash chromatography on silica gel (nHexane/EtOAc=7/3

General Procedure for the acid-catalysed Friedel-Crafts/lactonization reaction
The alkylating agent (5.5 mmol) was added in one portion to a stirred solution of the appropriate phenol (5.0 mmol) in acetic acid (3 mL). The system was kept under an argon atmosphere. The clear reddish solution was stirred at reflux temperature, until the substrate had been completely consumed (TLC and HPLC monitoring). Afterwards, the reaction mixture was concentrated under vacuum and the residue was purified by flash chromatography on silica gel to give the products as described below.

Calibration curves
From a stock solution of 250 μM DPPH • in MeOH or ACN, previously degassed with a N2 flow, ten standards at different concentrations from 0 to 110 μM were prepared. The absorbance (λmax = 517 nm) for each standard was measured in a Cary300 spectrophotometer or Shimadzu-UV-2401PC spectrophotometer and plotted versus the concentration of DPPH • . Figure

DPPH assay in methanol
Once the linearity of the monitored method at 517 nm was evaluate by the calibration curve of DPPH • concentration versus absorbance at 517 nm, 2 mL of 140 μM DPPH • stock solution (70 μM DPPH final concentration) were added to the degassed methanol solutions (2mL) of antioxidant, with a final concentration from 0 to 60 μM. After 60 minutes stirring at room temperature in the absence of light, the absorbance was measured at 517 nm. Figure SM

DPPH assay in acetonitrile
The assay was performed as described above, using as solvent the acetonitrile (ACN). Once the linearity of the monitored method at 517 nm was evaluate in this solvent through the calibration curve of DPPH • concentration versus absorbance at 517 nm, the absorbance measurements of each solution, containing a known concentration of antioxidant and DPPH • , were collected. Figure   Sequentially Table SM-3 and Table SM-4 show the corresponding regression lines with the values of R 2 as well as all the deducible parameters from rIC50.  The procedure used to determine k s was common to all solvents and compounds. A solution of DPPH • and the compound were prepared in nitrogen-purged solvents. Then, the decay of DPPH • in the presence of a known concentration of compound was followed at 517 nm on a Shimadzu-UV-2401PC spectrophotometer. The concentration of DPPH • was 8.5*10 -5 M and the compounds were always used in large excess over [DPPH • ]. The decay of the DPPH • absorbance was analysed as pseudo-first-order processes to yield kex/s -1 , using Sigma plot for Windows. The measurements were performed in triplicate. Plots of kex vs compound concentration is linear and its slopes gave the second-order rate constants, k s . The observed results are reported in Table SM-5.


extfieldsofstudy:
Materials Science
Physics

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Research of Physical and Mechanical Properties of SFRC by Top Ram Pressure

Ram pressure is one of the important factors which impacts the mixing process and top ram pressure of SFRC greatly. The effects of different top ram pressure on mixing process of SFRC have been researched by experiments. In the paper, the top ram pressure was changed from 0.3MPa to 0.6MPa respectively. And also the addition of short fibers was about 0phr~6phr. The experimental results indicated that SFRC had better physical and mechanical properties as top ram pressure was about 0.6MPa, and the addition of short fibers was about 3phr.

Introduction
Short fiber-rubber composite material (SFRC) is a kind of composites, which could be manufactured by the way of mixing rubber, short fibers and other fillers such as N330, SiO2, 4010NA etc. Because SFRC has good performances, it has been used in almost all kinds of rubber products in recent years [1~3]. Especially, SFRC has been applying to all parts of tires, such as tire tread, tire shoulder, tire wall [4~9], etc. While mixing is the first step and one of the most important steps of manufacturing SFRC, because mixing quality influences the coming process and products performances directly. Due to top ram pressure is an important factor which influences the mixing quality and physical and mechanical properties of SFRC, so the effects of top ram pressure on mixing process and physical and mechanical properties has been researched by experiments in this paper.

Testing samples.
The samples for performances testing were made in the following way. Pay attention to the orientation of short fibers during the vulcanization process of mixed rubber, then the samples should be made along the orientation of short fibers as shown in the Fig.1.

Results and Discussion
In order to research the effects of top ram pressure on the mixing process and physical and mechanical properties of SFRC, the top ram pressure was changed as 0.3MPa, 0.4MPa, 0.5MPa and 0.6MPa. Also, the addition of short fibers was changed as 0phr, 1phr, 3phr, 5phr and 6phr in the experiments. And the other experimental conditions were not changed. The experimental results have been shown in Fig.2, in which, • top ram pressure was 0.3MPa, ▼top ram pressure was 0.4MPa, ▲top ram pressure was 0.5MPa, ■top ram pressure was 0.6MPa.

The effects of top ram pressure on physical and mechanical properties
As vividly shown in the Fig.2, on the condition of same adding amount of the short fiber, the physical and mechanical properties including strength at 300% elongation, tensile strength, tear resistance, maximum elongation, permanent set at break and hardness of the mixed SFRC increase first and then decrease with the increasing of top ram pressure. And if the top ram pressure was 0.6MPa (shown as ■), the physical and mechanical properties of the SFRC would be best. The reason is that, if the top ram pressure was low, then the mixer rotors would pull rubber materials into the mixing room hardly, which would result to a weak mixing process for SFRC, and the mixing quality would be bad. But if the top ram pressure was high, it was good to enhance the mixing process of SFRC, due to the mixer rotors would pull rubber materials into the mixing room easily, it would make the electromotor with a high load status. As a result, it would decrease using life of the electromotor. Therefore, this means the top ram pressure is not the higher, the better. As what has been shown in the Fig.2, the proper top ram pressure was 0.6MPa.

The effects of fibers addition on physical and mechanical properties
As what has been vividly shown in the Fig.2, comparing the mixed rubber without short fibers and SFRC, the physical and mechanical properties of SFRC including strength at 300% elongation, tensile strength, tear resistance, maximum elongation, permanent set at break and hardness were better, which mean the short fibers had played a role in the reinforcing action. But if the short fibers addition was more than 3phr, the tensile strength, tear resistance, maximum elongation, permanent set at break would get worse, while strength at 300% elongation and hardness would get better and better. The reason is that, if more short fibers were added, due to modulus of short fibers was lager than that of rubber matrix, on one hand the flow ability of the mixed rubber would get worse, on the other hand, more short fibers couldn't disperse well in rubber matrix. So in general, it is not the more short fibers added, the physical and mechanical properties of SFRC are better. Therefore, according to the experimental results, the proper addition of short fibers is 3phr.

Conclusions
Top ram pressure impacts the mixing process and quality of mixed rubber greatly. During the mixing process, the maximum energy consumption, unit energy consumption and the discharging temperature would increase if top ram pressure increased or of short fibers addition increased. While the physical and mechanical properties would get better if the top ram pressure or the short fibers addition was proper. Therefore, according to the experimental results, the proper top ram pressure was 0.6MPa and addition of short fibers is 3phr.


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Design of an inherently-stable water oxidation catalyst

While molecular water-oxidation catalysts are remarkably rapid, oxidative and hydrolytic processes in water can convert their active transition metals to colloidal metal oxides or hydroxides that, while quite reactive, are insoluble or susceptible to precipitation. In response, we propose using oxidatively-inert ligands to harness the metal oxides themselves. This approach is demonstrated by covalently attaching entirely inorganic oxo-donor ligands (polyoxometalates) to 3-nm hematite cores, giving soluble anionic structures, highly resistant to aggregation, yet thermodynamically stable to oxidation and hydrolysis. Using orthoperiodate (at pH 8), and no added photosensitizers, the hematite-core complex catalyzes visible-light driven water oxidation for seven days (7600 turnovers) with no decrease in activity, far exceeding the documented lifetimes of molecular catalysts under turnover conditions in water. As such, a fundamental limitation of molecular complexes is entirely bypassed by using coordination chemistry to harness a transition-metal oxide as the reactive center of an inherently stable, homogeneous water-oxidation catalyst.

A current challenge in the development of molecular wateroxidation catalysts 1 is to overcome their inherent susceptibilities to oxidative or hydrolytic degradation under turnover conditions in water 2,3 . Advances in the past decade have led to remarkably fast rates of O 2 formation 4-6 , along with the parallel development of more stable catalysts 7 , better able to withstand strongly oxidizing conditions in water. Nevertheless, organic ligands are susceptible to oxidation 1,2,[8][9][10][11] , which, combined with hydrolysis of their active transition-metal centers, often results in the formation of colloidal metal oxides. Entirely inorganic polyoxometalate (POM)-based water-oxidation catalysts 12,13 , by contrast, are thermodynamically stable to oxidation [12][13][14][15] , can utilize earth-abundant metals 5,[14][15][16][17] , and feature remarkably rapid rates 5 . At the same time, molecular POM catalysts are stable to hydrolysis only under specific, albeit welldefined and by now, well-understood conditions, concerning variables such as pH and the nature and concentration of buffer [17][18][19] . Fundamentally, however, their catalytically active transition metals are in equilibrium with trace concentrations in the aqueous solvent 20 , which can lead to hydrolysis under nonoptimal conditions 18 . Hence, as advances in ligand design have led to impressively rapid rates and longer catalyst lifetimes under turnover conditions, catalyst stability nevertheless remains an ongoing topic of discussion and experiment 1,10,20 .
One reason for this heightened level of concern is that colloidal metal oxides can be extremely active [21][22][23] , such that considerable efforts are required to prove that the molecular catalyst, and not its products of decomposition in water, are the kinetically competent species in catalytic water oxidation. Given this situation, a compelling solution to catalyst stability might be to embrace the colloidal metal-oxide nanocrystals (NCs) themselves as thermodynamically stable water-oxidation catalysts. Apart from a few exceptions 23 , however, colloidal metal oxides are either insoluble at most pH values in water, or rapidly aggregate and precipitate from water under turnover conditions. And, despite impressive advances in solvothermal syntheses of metal-oxide NCs 24 , the requisite organic stabilizing ligands are not only susceptible to oxidation, but usually limit solubility in water and block access to the metal-oxide surface.
In this context, we recently discovered that heteropolytungstate cluster anions (POMs) could serve as covalently attached oxodonor ligands for 6-nm anatase-TiO 2 NCs 25 , giving water-soluble POM-complexed nanostructures. We now deploy Fe(III)-substituted [α-P V W VI 11 O 39 ] 7cluster anions as oxo-donor ligands for hematite (α-Fe 2 O 3 ) cores, giving water-soluble catalysts, 1, uniquely positioned between molecular iron-oxide clusters 26 and colloidal hematite 27,28 . The new catalyst features 3-nm hematite (α-Fe 2 O 3 ) cores comprised of ca. 300 Fe atoms, sufficiently large to possess the visible-light semiconductor properties of hematite. Unlike colloidal hematite, however, covalent coordination of each α-Fe 2 O 3 core by ca. 15 cluster anions renders the POMcomplexed structures stable to aggregation in water, giving optically transparent solutions at pH values of 2.5 to 8. Moreover, fitted with entirely inorganic tungsten(VI)-oxide ligands, and formed in water at 220°C, 1 is thermodynamically stable to both oxidative degradation and hydrolysis. As an inherently stable visible-light activated water-oxidation catalyst, 1 is capable of continuous operation for 7 days under turnover conditions (corresponding to 7600 turnovers) with no decrease in activity.

Results
Inorganic coordination complexes of hematite. Complex 1 is prepared by converting micron-sized particles of γ-FeO(OH) to α- remain bound via bridging oxo linkages to 3-nm hematite cores ( Fig. 1a and Supplementary Figures 1-7). The reaction gives an orange, optically transparent pH-7 solution of 1 (Fig. 1b, left inset). Dynamic light scattering (DLS) of the clear-orange solution reveals a number-weighted hydrodynamic radius of 1.9 nm (Fig. 1b). Cryogenic-TEM images 29 of the same (vitrified) solution (right inset to Fig. 1b) reveal numerous freely diffusing particles with an average size of 2.8-3.0 nm, too small for resolution of their surface structures in cryo-TEM images (additional images in Supplementary Figure 8). (This limitation is consistent with extensive studies of POMs on gold nanoparticles, in which even well-ordered POM monolayers are not discernible on gold cores smaller than ca. 5 nm 29 .) The cores of 1 are single NCs of hematite (α-Fe 2 O 3 ). Highresolution TEM images (Fig. 1c) reveal an inter-planar spacing of 2.69 Å, in agreement with the (104) crystal planes of hematite 30 . Indexing of the well-defined rings found in electron diffraction of dry samples precisely matches hematite ( Supplementary Figure 9a) 31 , and the related dark-field images reveal individual 2.8 ± 0.5 nm ( ± denotes s.d.) diameter NCs (Supplementary Figure 10). The hematite structure was further confirmed by powder X-ray diffraction (XRD) 30 , for which the Debye-Scherrer equation 32 gave a crystallite size of 3.5 ± 0.5 nm ( Supplementary  Figures 9b and 11).
Isolation and stability to aggregation. To isolate pure samples of 1, a clear-orange solution (inset to Fig. 1b) was made 2 M in NaCl. This gave a cloudy solution of salted-out 1, an orange-red solid isolated by centrifugation. Re-dissolution of 1 in pure water (10 mL) returned clear-orange solutions, even after multiple cycles of NaCl addition, centrifugation, and re-dissolution (Supplementary Figure 2). This solubility and remarkable stability to  aggregation differs dramatically from the properties of electrostatically stabilized colloids. Behaving more like a molecular macroanion, the hydrated Na + salt of 1 can be stored indefinitely, and then readily dissolved in water. These findings provided the first indication that, as shown in Fig. 1a, heteropolytungstate cluster anions are covalently bound to the hematite cores.
Cluster-anion ligands coordinated to hematite cores of 1. Energy-dispersive X-ray spectroscopic (EDX) analysis of 1 ( Differential pulse voltammetry (DPV) 25 performed after adding LiClO 4 (0.1 M) to aqueous solutions of 1 (Fig. 2c), provided further support for the presence of [α-PW 11 O 39 Fe] anions at the hematite surface. While conceptually analogous to electrochemical studies of ferrocene-covered SiO 2 nanoparticles 33 , to our knowledge, the observation of reversible redox chemistries of ligands bound to metal-oxide NCs in solution has few precedents in the literature 25 . It was made possible here by the abundance of cluster anions on the hematite surface, in combination with the water solubility imparted by their negative charges and numerous alkali-metal counter-cations. After adding LiClO 4 (0.1 M), differential pulse voltammetry (DPV) revealed reversible redox processes consistent with the presence of the cluster anions identified by ESI-MS (DPV data for the independently prepared molecular cluster anions are provided in Supplementary Figure 15b).
Surface coverage by the POM anions, based on a reasonable footprint of 1.9 nm 2 , places 15 POMs on the surface of an (idealized) spherical 3-nm-diameter hematite core (Supplementary Table 1). Such a structure would contain 165 W atoms and 279 Fe atoms, giving a relative atomic composition of 37% W and 63% Fe, nicely matching the %-atom values observed by EDX (Fig. 2a). The W to Fe ratio also gives ca. 18-20 Fe atoms per POM ligand.
Not only is 1 remarkably stable to aggregation, it is soluble at pH values of 2.5-8. Over this wide pH range, its largely negative zeta potential values (ζ, −35 to −40 mV) remain pH-invariant (Fig. 2d). By contrast, colloidal α-Fe 2 O 3 precipitates at its isoelectric point (pH 5.5), at which ζ = 0 mV 34 . These findings represent three independent lines of evidence for strong coordination of the POM ligands to the α-Fe 2 O 3 cores. Given these inert linkages, metathesis of Na + counter-cations (of the POMs) by n-R 4 N + (R = hexyl or octyl) was used to render 1 organic-solvent soluble. This cation-exchange proceduretypical of POM salts-gave optically transparent MeCN or MeOH solutions with no loss of POM ligands (Supplementary Figure 16), further evidence for their covalent attachment to the hematite cores.
It is extraordinarily difficult to precisely determine the atomic connectivities of molecules bound to colloidal NCs. However, the presence of a μ 2 -oxo linkage between Fe(III) ions in the known oxo-  Figure 17). Notably, these W4f peaks are comparable with those of 2 ( Supplementary Figures 18 and 19), consistent with the presence of Keggin-anion derived ligands connected to the surface of 1 via μ 2 -oxo linkages.
This was investigated in more detail by FTIR spectroscopy (Fig. 3). The IR-allowed vibrational modes of the central PO 4 moieties within Keggin-derived structures are highly sensitive to changes in symmetry of the cluster anion. Removal of a single W (VI) ion from the plenary-Keggin anion, [α-PW 12 O 40 ] 3-, reduces the local symmetry of the central PO 4 moiety from T d to C 3v . As a result, rather than a single IR-active mode at 1080 cm -1 , two IRactive PO 4 modes are observed for mono-lacunary [α-PW 11 O 39 ] 7-. And, after complexing a transition-metal cation, the difference in energy between the two IR-active modes depends on cation size, and the degree to which it fits within the lacunary anion's pentacoordinate binding site 36 . As the ion is pulled farther out from the binding pocket, the local symmetry around the central PO 4 moiety deviates from Td, leading to a larger difference in energy between the two IR-active PO 4 bands. Hence, splitting of the PO 4 mode can be used to identify the ligand environments of substituted transition-metal cations.
The precise match between the PO 4 bands 36 of the POM ligands on 1 (1090 and 1051 cm −1 ; Fig. 3a) with the corresponding PO 4 bands of 2 (1090 and 1050 cm −1 ; Fig. 3b), is consistent with μ 2 -oxo linkages between the POM ligands and the hematite cores. Combined with the EDX data in Fig. 2a In the present work, the covalent attachment of POM ligands to the hematite cores of 1 gives substitutionally inert structures that occupy a unique position at the interface between molecular iron-oxide clusters and electrostatically stabilized colloidal ironoxide NCs. We now show that, when used as a soluble photocatalyst for visible-light driven water oxidation, 1 is inherently stable under turnover conditions in water.
Catalytic water oxidation. The activity of 1 as a visible-light water-oxidation catalyst was explored by irradiating pH-8 solutions of 1 with visible light (150 W Xe lamp, cutoff λ ≥ 420 nm, Supplementary Figures 21 and 22). Four oxidants were evaluated: Ce(IV), Ag + , S 2 O 8 2-, and periodiate (I VII O 4 -). Ce(IV) was not suitable as it is only stable at pH values below 1, at which hematite itself dissolves. Although Ag + is soluble at neutral pH values, these large cations form strong ion pairs with the negatively charged POM ligands, leading to precipitation at desired Ag Although written as IO 4 -, a recent report shows 43 that its dominant form in water is actually orthoperiodate, H 5 IO 6 , which behaves as a polyprotic acid, with pKa 1 , pKa 2 , and pKa 3 values of ca. 1, 7.5, and 11, respectively. For simplicity, entries in Table 1 refer to added periodate (IO 4 -).
The greater reactivity of IO 4relative to S 2 O 8 2- (Table 1) is not unique to visible-light driven reactions of 1. Notably, IO 4is also more effective than S 2 O 8 2in trapping photoexcited electrons from visible-light irradiated WO 3 Table 2). At the same time, when using IO 4 -11 , decomposition or oxo-transfer reactions 46 , that could generate O 2 without removing four electrons from water, must be ruled out 47,48 . This required numerous control experiments (see Supplementary Figure 25 and Table 3), necessitated by the fact that the oxide ligands of periodate equilibrate rapidly with water, precluding the use of 18   Rate optimization and stability under turnover conditions. Unlike most polyoxometalate-based water-oxidation catalysts, 1 is stable in water over a wide range of pH values, from 2.5 to 8. And, in contrast to colloidal hematite that precipitates from solution at its isoelectric point (i.e., at pH 5.5), 1 is soluble over this entire pH range (see Fig. 2d). Hence, unlike most purely molecular or traditional colloidal catalysts, the activity of 1 can be investigated over a wide range of pH values. The results (Fig. 4a) reveal an approximate doubling of rate from pH values of 5 to 8. At pH 8, the rate of O 2 formation is 800 ± 50 µmol g −1 h −1 (at λ ≥ 420 nm using a 150 W Xe lamp), somewhat exceeding the fastest reported rates for visible-light driven water oxidation by colloidal α-Fe 2 O 3 (see Supplementary Table 4 for reported values and related light sources).

Fe-OH 2 H H
The change in pH from 5 to 8 spans the isoelectric point of hematite (near pH 5.5; Fig. 2d). As such, the increase in rate may correlate with deprotonation of water molecules bound to the hematite surface, to give more reactive (negatively charged) hydroxide ligands, in combination with the more favorable, pHdependent Gibbs free energy for water oxidation itself. For periodate to trap photoexcited electrons, it must diffuse to within a close proximity to the α-Fe 2 O 3 surface. The cluster-anion ligated surface of 1, including [H 3 I VII O 6 ] 2-(orthoperiodate-the dominant periodate species present at pH 8-drawn to scale), and Na + counter-cations (without their hydration shells), is illustrated in Fig. 4b The rate of visible-light driven water oxidation by 1 is enhanced by the relatively small size of the hematite cores, which is critically important 28 due to the short, 2-4 nm, hole-diffusion length 55 of α-Fe 2 O 3 . This leads to a quantum yield of 3.9%, closely matching values reported for optimized reactions of similarly sized colloidal hematite 28,56 .
A preliminary schematic of reasonable mechanistic steps is provided in Fig. 4c. Trapping of an excited electron by [H 3 I VII O 6 ] 2-(the dominant form of periodate at pH 8) 43 would result in oxidation of a surface Fe III -OH moiety to Fe IV =O (A and B, respectively, in Fig. 4c), a species recently  the solutions remained optically transparent. After each 8-h reaction, the catalyst was quantitatively isolated by salting out with NaCl (2 M) and centrifugation, followed by re-dissolution in fresh water (Supplementary Figure 28a). Notably, this had no effect on its activity. The same remarkable retention of activity was observed in a single 7-day (1-week) reaction (7600 turnovers; Fig. 4d). No decrease in activity was observed. The TOF remained constant at 44 ± 1 h -1 , the solution remained optically transparent (inset to Fig. 4d), and no aggregation was observed by DLS (Supplementary Figure 29).
The TON of 7600 is much larger than that reported for colloidal hematite. For example, under identical conditions, the initial rate of O 2 formation by 5-nm colloidal α-Fe 2 O 3 (no POM ligands) 56 was ca. 320 µmol g −1 h −1 , but decreased dramatically within a few hours due to aggregation processes typical of colloidal metal oxides in water (Supplementary Figure 28b). Moreover, the present TON is more than seven times that reported for the most stable, water-soluble Fe-based catalysts 11 which, although much faster than 1 (with respect to TOF), become inactive within a few hours under turnover conditions in water. And, while acknowledging that 1 contains ca. 300 Fe atoms, many more than typically found in traditional molecular catalysts, its relatively small (ca. 20 Å) α-Fe 2 O 3 center is   nevertheless large enough to retain the photochemical properties of bulk hematite. It is from this perspective that 1 can be viewed as a soluble complex of a reactive metal-oxide core.

Discussion
Oxidatively inert heteropolytungstate cluster anions serve as covalently coordinated oxo-donor ligands for 3-nm hematite (α-Fe 2 O 3 ) cores, giving anionic complexes soluble in water over a wide range of pH values (from 2.5 to 8), and that catalyze visiblelight driven water oxidation with no need for added photosensitizers. Like molecular macroanions, 1 is highly resistant to aggregation processes that typically lead to the precipitation of electrostatically stabilized hematite and other colloidal metal oxides. And, formed by reaction with entirely inorganic tungstenoxide-based ligands at 220°C in water, 1 is inherently (thermodynamically) stable to the oxidative and hydrolytic processes that can limit the active lifetimes of molecular water-oxidation catalysts. As such, 1 can continuously catalyze water oxidation for 7 days (1 week) with no detectable decrease in activity. Moreover, the method used to prepare 1 is not limited to iron oxide, but can be modified according to the pH-controlled aqueous speciation chemistries of numerous other transition-metal ions. As such, the covalent coordination of oxidatively inert polyoxometalate ligands to metal-oxide nanocrystal cores represents a conceptually new and general approach to the design of inherently stable water-oxidation catalysts. Visible-light driven water oxidation. Photochemical O 2 production was carried out in a gas-tight quartz cuvette connected to an upper glass bulb with a headspace volume of 16 mL. Carefully weighed samples of 1 were dissolved in 2.7 mL of water along with sodium periodate (NaIO 4 ; 12.8 mg in 0.1 mL of water) to give a final NaIO 4 concentration of 20 mM. The addition of NaIO 4 led to a drop in pH from 6.5 to 5, and either 0.2 N KOH or 0.2 N HCl solutions were used to adjust the pH to desired values (see Fig. 4a). The headspace within the cuvette was evacuated and refilled with pure Ar (g) four times to remove most of the air, after which the solution was purged with Ar (g) for 30 min to remove dissolved oxygen. The solution was then irradiated with a 150 W Xe lamp (USHIO Inc. Japan), after inserting a 420-nm long-pass filter between the light source and the cuvette, which was held at a distance of 12 cm from the light source. The illumination area was 2 cm 2 and the average light intensity was 565 mW cm −2 at λ = 450 nm measured using a 1928-C Optical Power Energy Meter (Newport Corp.) equipped with a model 919P-250-35 Thermopile sensor (UV-calibrated silicon detector). The headspace gas (0.5-mL volume portions) was injected every 2 hours into a gas chromatograph (Focus GC, Thermo Scientific) operating at isothermal conditions (40°C) using a ShinCarbon ST micropacked column (0.53-mm diameter, 2-m length), and equipped with a thermal conductivity detector (TCD) and Ar as carrier gas. Moles of O 2 per gram reported for 1 were calculated based on the mass of its α-Fe 2 O 3 cores, which comprised ca. 50% of the total mass of 1.
Water oxidation for 7 days under turnover conditions. A solution of 1 (5.4 μM) and NaIO 4 (20 mM) in 3 mL of water at pH 8 (adjusted using 0.2 N KOH) was degassed as described above and irradiated with visible light (λ > 420 nm) for 1 day, during which, amounts of O 2 in the headspace were quantified at regular intervals (see Fig. 4d). After 1 day, 6.4 mg of solid NaIO 4 dissolved in 0.1 mL of water was added to the solution (an additional 10 mM concentration of IO 4 -) and the reaction continued for a second day. After day 2, 1 was quantitatively separated from accumulated iodate (IO 3 -; ca. 5.5 mM) by making the solution 0.5 M in NaCl, and isolating the salted-out catalyst by centrifugation. (A control experiment later carried out after recharging the supernatant solution with periodate, followed by irradiation, showed no activity (i.e., no O 2 in 8 h). This demonstrated that possibly unidentified soluble components were not responsible for the catalysis.) The pellet of 1 isolated after day 2 was then dissolved in 3 mL of water containing freshly added periodate (20 mM), adjusted to pH 8, degassed, and irradiated for day 3.
(Similar separations of 1 from accumulated IO 3were repeated after days 4 and 6.) After days 3 and 5, additional 10 mM concentrations of IO 4were added. Turnover numbers were calculated based on the moles of O 2 produced per mole of 1.

Data availability
All data generated or analyzed during this study are included in this published article (and its supplementary information files).