Optically Pure Calixarenyl Phosphine via Stereospecific Alkylation on Evans’ Oxazolidinone Moiety

A convenient protocol for the synthesis of 25,26,27-tribenzoyl-28-[((S)-1-diphenylphos- phanyl-propan-2-yl)oxy]-calix[4]arene via stereospecific methylation on Evans’ oxazolidinone moiety was reported. According to the 13C NMR analysis of this phosphine, the calix[4]arene skeleton adopted a 1,3-alternate conformation. The latter conformation of the macrocycle and the (S)-chirality of the carbon atom bearing the methyl substituent were confirmed by a single-crystal X-ray diffraction study. After coordination of the phosphinated ligand to the dimeric [RuCl2(p-cymene)]2 organometallic precursor, the resulting arene–ruthenium complex was tested in the asymmetric reduction of acetophenone and alcohol was obtained with modest enantiomeric excess.

Furthermore, calix [4]arenes are dynamic molecules that can exist under the following four conformational isomeric structures: cone, partial cone, 1,2-alternate, and 1,3-alternate (Figure 1).Ring inversion occurs through "oxygen-through-the-annulus rotation" [13] and it is well-established that the introduction of propyl substituents at the phenolic positions is sufficient to block this rotation and lock the conformation of calix [4]arenes [14].
Furthermore, calix [4]arenes are dynamic molecules that can exist under the following four conformational isomeric structures: cone, partial cone, 1,2-alternate, and 1,3-alternate (Figure 1).Ring inversion occurs through "oxygen-through-the-annulus rotation" [13] and it is well-established that the introduction of propyl substituents at the phenolic positions is sufficient to block this rotation and lock the conformation of calix [4]arenes [14].With appropriate functionalization, generic calix [4]arene provides a useful preorganization platform for the preparation of optically active phosphinated ligands.As examples, these can be used in the asymmetric reduction of olefins or in the asymmetric formation of carbon-carbon bonds (Figure 2).With appropriate functionalization, generic calix [4]arene provides a useful preorganization platform for the preparation of optically active phosphinated ligands.As examples, these can be used in the asymmetric reduction of olefins or in the asymmetric formation of carbon-carbon bonds (Figure 2).Examples of reported asymmetric reactions involving phosphinated calix [4]arenes as optically active ligands.
In the case of asymmetric rhodium-catalyzed hydrogenation of methyl ester (Z)-N-acetyl-dehydro-phenylalanine, recently, we studied the positioning of the two phosphito units on the calix [4]arene platform and its effect on the transfer of chirality from the ligand to the substrate (Equation (2) in Figure 2).The two phosphito units were grafted either on distal (B) and proximal (D) aromatics of the lower rim or on distal (E) aromatics of the upper rim.The catalytic system was generated in situ starting from [Rh(cod)2]BF4 (1 mol%) and the ligand.The runs were performed in CH2Cl2 at room temperature under 5 bar of hydrogen for 24 h.Under the latter catalytic conditions, the pro-chiral olefin was fully reduced and the enantioselectivities increased in the order E (ee 57%) < D (ee = 62%) < B (ee = 91%).These differences could be explained by steric factors generated by the second coordination sphere of the ligand, i.e., by the calix [4]arene skeleton.In accordance with molecular models, the more sterically con- For instance, for the asymmetric rhodium-catalyzed hydrogenation of methyl-(Z)-2-(acetamido)acrylate (Equation (1) in Figure 2), van Leeuwen and co-workers reported the use of calixarenyl diphosphite A (Figure 3) based on the (R,R)-2,2-dimethyl-α,α,α',α'tetraphenyldioxolane-4,5-dimethanol moiety.The catalytic system was generated in situ from the ligand and [Rh(nbd) 2 ]BF 4 (nbd = bicyclo[2.2.1]hepta-2,5-diene) as an organometallic precursor (1 mol%) in dichloromethane.After 20 h at room temperature under 5 bar of hydrogen, the (R)-alanine derivative was quantitatively obtained with an enantiomeric excess (ee) of 94% [15].A slightly higher enantioselectivity (ee = 98%) was obtained by Sandoval and co-workers using [Rh(cod) 2 ]BF 4 (1 mol%; cod = 1,5-cyclooctadiene) and the non-conformationally flexible calixarenyl diphosphite B (Figure 3) as the catalytic system.The run was performed in dichloromethane under 5 bar of hydrogen at 30 • C for 11 h [16].
In the case of asymmetric rhodium-catalyzed hydrogenation of methyl ester (Z)-Nacetyl-dehydro-phenylalanine, recently, we studied the positioning of the two phosphito units on the calix [4]arene platform and its effect on the transfer of chirality from the ligand to the substrate (Equation (2) in Figure 2).The two phosphito units were grafted either on distal (B) and proximal (D) aromatics of the lower rim or on distal (E) aromatics of the upper rim.The catalytic system was generated in situ starting from [Rh(cod) 2 ]BF 4 (1 mol%) and the ligand.The runs were performed in CH 2 Cl 2 at room temperature under 5 bar of hydrogen for 24 h.Under the latter catalytic conditions, the pro-chiral olefin was fully reduced and the enantioselectivities increased in the order E (ee 57%) < D (ee = 62%) < B (ee = 91%).These differences could be explained by steric factors generated by the second coordination sphere of the ligand, i.e., by the calix [4]arene skeleton.In accordance with molecular models, the more sterically constrained active species (encapsulation of the catalytic center inside a molecular pocket), obtained when the diphosphite B was employed, led to the more efficient chirality transfer from the ligand to the substrate [18].
strained active species (encapsulation of the catalytic center inside a molecular pocket), obtained when the diphosphite B was employed, led to the more efficient chirality transfer from the ligand to the substrate [18].Regarding the carbon-carbon bond formation, the most popular reaction is the palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate, released generally with the N,O-bis(trimethylsilyl)acetamide and acetate salt as bases (Equation (3) in Figure 2).In this context, diphosphine F, in which the calix [4]arene platform exhibits an inherent chirality [19], led to a moderate enantiomeric excess of 67% [20].A higher enantioselectivity (ee = 82%) was reported by Harvey, Jugé, and co-workers using the C2 symmetry P-chirogenic diphosphine G, [Pd(η 3 -C3H5)Cl]2 as an organometallic precursor and n BuLi as the base [21].The best enantiomeric excess value (ee = 86%) was measured by Manoury and co-workers using the in situ catalytic system resulting from calixarenyl di-ferrocenylphosphine H and [Pd(η 3 -C3H5)Cl]2 (6 mol%) with MOAc (M = Na or K) as the base.With this system, the enantioselectivity of the product strongly depended on the acetate counterion, and the highest enantiomeric excess value was measured when KOAc was employed [22].
In 2019, our group reported the rhodium-catalyzed asymmetric hydroformylation of styrene (Equation (4) in Figure 2) with diphosphite E, in which the two phosphito units were grafted on the upper rim of the calix [4]arene platform.Using the [Rh(acac)(CO)2] source of metal (0.1 mol%) and an excess of ligand (5 equiv./Rh)after 24 h at 50°C in toluene under 20 bar of syngas, the aldehydes were formed in a conversion of 82%, and the 2-phenylpropanal was observed with a b/l ratio of 88:12 and an ee of 89%.Molecular models reveal that the most favorable conformation of the trigonal bipyramidal [RhH(CO)2(E)] active species has the rhodium atom turned towards the exterior of the Regarding the carbon-carbon bond formation, the most popular reaction is the palladium-catalyzed asymmetric allylic alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate, released generally with the N,O-bis(trimethylsilyl)acetamide and acetate salt as bases (Equation (3) in Figure 2).In this context, diphosphine F, in which the calix [4]arene platform exhibits an inherent chirality [19], led to a moderate enantiomeric excess of 67% [20].A higher enantioselectivity (ee = 82%) was reported by Harvey, Jugé, and co-workers using the C 2 symmetry P-chirogenic diphosphine G, [Pd(η 3 -C 3 H 5 )Cl] 2 as an organometallic precursor and n BuLi as the base [21].The best enantiomeric excess value (ee = 86%) was measured by Manoury and co-workers using the in situ catalytic system resulting from calixarenyl di-ferrocenylphosphine H and [Pd(η 3 -C 3 H 5 )Cl] 2 (6 mol%) with MOAc (M = Na or K) as the base.With this system, the enantioselectivity of the product strongly depended on the acetate counterion, and the highest enantiomeric excess value was measured when KOAc was employed [22].
In 2019, our group reported the rhodium-catalyzed asymmetric hydroformylation of styrene (Equation (4) in Figure 2) with diphosphite E, in which the two phosphito units were grafted on the upper rim of the calix [4]arene platform.Using the [Rh(acac)(CO) 2 ] source of metal (0.1 mol%) and an excess of ligand (5 equiv./Rh)after 24 h at 50 • C in toluene under 20 bar of syngas, the aldehydes were formed in a conversion of 82%, and the 2phenylpropanal was observed with a b/l ratio of 88:12 and an ee of 89%.Molecular models reveal that the most favorable conformation of the trigonal bipyramidal [RhH(CO) 2 (E)] active species has the rhodium atom turned towards the exterior of the cavity with the apical hydride and the equatorial carbon monoxide ligands located in a chiral hindered environment generated by the two binaphthyl moieties [23].
In this context, and to the best of our knowledge, there is no example of a ruthenium catalyst based on optically calixarenyl phosphine achieving the transfer hydrogenation of ketones.In continuation of our quest to develop a new macrocyclic ligand, herein we report the synthesis of phosphine 1 (Figure 4) and its application in the asymmetric ruthenium-catalyzed reduction of ketones.
cavity with the apical hydride and the equatorial carbon monoxide ligands located in a chiral hindered environment generated by the two binaphthyl moieties [23].
In this context, and to the best of our knowledge, there is no example of a ruthenium catalyst based on optically calixarenyl phosphine achieving the transfer hydrogenation of ketones.In continuation of our quest to develop a new macrocyclic ligand, herein we report the synthesis of phosphine 1 (Figure 4) and its application in the asymmetric ruthenium-catalyzed reduction of ketones.

Scheme 1. Synthesis of borane adduct 8.
Synthesis of the targeted borane adduct 8 started with the grafting of Evans' oxazolidinone on the partial cone 25,26,27-tribenzoyl-28-hydroxycalix [4]arene (2).Then, a Williamson substitution was carried out in DMF in two steps.First, a deprotonation of the calixarenyl phenol with NaH followed by the addition of (R)-4-benzyl-3-(2-bromoacetyl)oxazolidin-2-one (3) [25,26].After purification, the optically pure calixarene 4 was isolated in 59% yield.NMR spectra confirmed the presence of the oxazolidinone substituent.In addition, careful examination of the 13 C NMR spectrum revealed the presence of two signals at 37.30 and 37.25 ppm for the ArCH2Ar methylene carbons.According to the observations of de Mendoza, Prados, and co-workers, such 13 C NMR values are typical for CH2 groups bridging anti-oriented phenol rings [27], which implies a 1,3-alternate conformation of the calix [4]arene skeleton.
Having in hand the optically pure calixarenyl oxazolidinone 4, asymmetric methylation, induced by the chiral auxiliary, was achieved on the methylenic position using
cavity with the apical hydride and the equatorial carbon monoxide ligands located in a chiral hindered environment generated by the two binaphthyl moieties [23].
In this context, and to the best of our knowledge, there is no example of a ruthenium catalyst based on optically calixarenyl phosphine achieving the transfer hydrogenation of ketones.In continuation of our quest to develop a new macrocyclic ligand, herein we report the synthesis of phosphine 1 (Figure 4) and its application in the asymmetric ruthenium-catalyzed reduction of ketones.

Scheme 1. Synthesis of borane adduct 8.
Synthesis of the targeted borane adduct 8 started with the grafting of Evans' oxazolidinone on the partial cone 25,26,27-tribenzoyl-28-hydroxycalix [4]arene (2).Then, a Williamson substitution was carried out in DMF in two steps.First, a deprotonation of the calixarenyl phenol with NaH followed by the addition of (R)-4-benzyl-3-(2-bromoacetyl)oxazolidin-2-one (3) [25,26].After purification, the optically pure calixarene 4 was isolated in 59% yield.NMR spectra confirmed the presence of the oxazolidinone substituent.In addition, careful examination of the 13 C NMR spectrum revealed the presence of two signals at 37.30 and 37.25 ppm for the ArCH2Ar methylene carbons.According to the observations of de Mendoza, Prados, and co-workers, such 13 C NMR values are typical for CH2 groups bridging anti-oriented phenol rings [27], which implies a 1,3-alternate conformation of the calix [4]arene skeleton.
Having in hand the optically pure calixarenyl oxazolidinone 4, asymmetric methylation, induced by the chiral auxiliary, was achieved on the methylenic position using Scheme 1. Synthesis of borane adduct 8.
Synthesis of the targeted borane adduct 8 started with the grafting of Evans' oxazolidinone on the partial cone 25,26,27-tribenzoyl-28-hydroxycalix [4]arene (2).Then, a Williamson substitution was carried out in DMF in two steps.First, a deprotonation of the calixarenyl phenol with NaH followed by the addition of (R)-4-benzyl-3-(2bromoacetyl)oxazolidin-2-one (3) [25,26].After purification, the optically pure calixarene 4 was isolated in 59% yield.NMR spectra confirmed the presence of the oxazolidinone substituent.In addition, careful examination of the 13 C NMR spectrum revealed the presence of two signals at 37.30 and 37.25 ppm for the ArCH 2 Ar methylene carbons.According to the observations of de Mendoza, Prados, and co-workers, such 13 C NMR values are typical for CH 2 groups bridging anti-oriented phenol rings [27], which implies a 1,3-alternate conformation of the calix [4]arene skeleton.
Having in hand the optically pure calixarenyl oxazolidinone 4, asymmetric methylation, induced by the chiral auxiliary, was achieved on the methylenic position using potassium bis(trimethylsilyl)amide (KHMDS) as the base and methyl iodide as the electrophile [28,29].The methylated calixarene 5 was isolated in 46% yield as a unique diastereoisomer, as shown by its 1 H NMR spectrum, where only one signal could be observed at 1.62 ppm (doublet with 3 J HH = 6.5 Hz) for the grafted methyl group.This may be explained by the coordination of the potassium cation between the enolate intermediate and the carbonyl group of the carbamate function.This flat conformation induced a more accessible approach for steric reasons of the electrophile (MeI) on the opposite side (si-face) of the benzyl group (Scheme 2) [30].
potassium bis(trimethylsilyl)amide (KHMDS) as the base and methyl iodide as the trophile [28,29].The methylated calixarene 5 was isolated in 46% yield as a unique stereoisomer, as shown by its 1 H NMR spectrum, where only one signal could be served at 1.62 ppm (doublet with 3 JHH = 6.5 Hz) for the grafted methyl group.This ma explained by the coordination of the potassium cation between the enolate interme and the carbonyl group of the carbamate function.This flat conformation induced a m accessible approach for steric reasons of the electrophile (MeI) on the opposite (si-face) of the benzyl group (Scheme 2) [30].In agreement with the work of Prashad and co-workers [31], after treatment o ans' compound 5 with NaBH4 in THF/H2O, oxazolidinone-free calixarene 6 was iso in 72% yield.Its 13 C NMR spectrum displayed a singlet at 67.47 ppm attributed to CH2OH group resulting from the cleavage of the chiral auxiliary.Iodide derivative 7 then obtained by reacting 6 with iodine in the presence of imidazole and phenylphosphine.After purification, calixarene 7 was isolated in 72% yield.The pres of the iodide atom was confirmed by its 13 C NMR spectrum, in which the CH2I signal observed at 8.89 ppm.
This study revealed that the calix [4]arene platform adopted a 1,3-alternate co mation, in which the opposite phenoxy rings displayed dihedral angles of 20.30° 29.75°, respectively.The separations between the aromatic carbon atoms of opp phenolic rings were 6.339 (C5-C33) and 6.513 Å (C19-C47).Furthermore, the X diffraction study unambiguously confirmed the (S)-configuration of the methy carbon atom (C49; Flack parameter of 0.03 (13) [34]).In agreement with the work of Prashad and co-workers [31], after treatment of Evans' compound 5 with NaBH 4 in THF/H 2 O, oxazolidinone-free calixarene 6 was isolated in 72% yield.Its 13 C NMR spectrum displayed a singlet at 67.47 ppm attributed to the CH 2 OH group resulting from the cleavage of the chiral auxiliary.Iodide derivative 7 was then obtained by reacting 6 with iodine in the presence of imidazole and triphenylphosphine.After purification, calixarene 7 was isolated in 72% yield.The presence of the iodide atom was confirmed by its 13 C NMR spectrum, in which the CH 2 I signal was observed at 8.89 ppm.
Interestingly, careful examination of the structure revealed that the benzoyl aromatic ring attached to the oxygen atom O3 was oriented towards the macrocycle cavity and was located on the bisector of the angle formed by the two phenolic planes, with dihedral angles of 10.67 • and 11.43 • , respectively.Similarly, the two aromatic cycles of the benzoyl groups attached to the oxygen atoms O1 and O5 were embedded into the calixarenyl cavity with a dihedral angle of 39.51 • .
Interestingly, careful examination of the structure revealed that the benzoyl aromatic ring attached to the oxygen atom O3 was oriented towards the macrocycle cavity and was located on the bisector of the angle formed by the two phenolic planes, with dihedral angles of 10.67° and 11.43°, respectively.Similarly, the two aromatic cycles of the benzoyl groups attached to the oxygen atoms O1 and O5 were embedded into the calixarenyl cavity with a dihedral angle of 39.51°.

Synthesis of the Ruthenium Complex and Its Catalytic Activity
Finally, ruthenium complex 9 was synthetized in two steps from borane adduct 8 without isolation of P(III) intermediate 1 (Scheme 3).First, protected calixarenyl phos- Interestingly, careful examination of the structure revealed that the benzoyl aromatic ring attached to the oxygen atom O3 was oriented towards the macrocycle cavity and was located on the bisector of the angle formed by the two phenolic planes, with dihedral angles of 10.67° and 11.43°, respectively.Similarly, the two aromatic cycles of the benzoyl groups attached to the oxygen atoms O1 and O5 were embedded into the calixarenyl cavity with a dihedral angle of 39.51°.

Synthesis of the Ruthenium Complex and Its Catalytic Activity
Finally, ruthenium complex 9 was synthetized in two steps from borane adduct 8 without isolation of P(III) intermediate 1 (Scheme 3).First, protected calixarenyl phos-

Synthesis of the Ruthenium Complex and Its Catalytic Activity
Finally, ruthenium complex 9 was synthetized in two steps from borane adduct 8 without isolation of P(III) intermediate 1 (Scheme 3).First, protected calixarenyl phosphine borane 8 was refluxed in methanol [35], and the reaction was monitored by TLC until full conversion, which was observed after 7 h.The formation of deprotected phosphine 8 was confirmed by 31 P NMR analysis carried out on the crude reaction mixture, which showed a shift of the unique signal from 11.3 ppm for 8 to −22.2 pm for 1, in agreement with the value reported for the 1-diphenylphosphinopropan-2-yl acetate (−22 ppm) [36].The ligand (1 equivalent) was then reacted with the dimeric [RuCl 2 (p-cymene)] 2 organometallic precursor (0.5 equivalent) in dichloromethane.After recrystallization, ruthenium complex 9 was isolated in 72% yield.Its 31 P spectrum displayed an important upfield shift from −22.2 ppm in the free ligand to 17.2 ppm for the complex.It is interesting to note that the p-cymene ligand showed in the 13 C NMR spectrum a desymmetrization of its four aromatic CH atoms, which appeared as four signals at 91.25, 89.61, 86.65, and 84.23 ppm.In addition, the two CH 3 of the isopropyl group were, in the 1 H NMR spectrum, unusually shielded at 0.71 and 0.90 ppm, compared with the classical chemical shift around 0.90 ppm [37,38].Finally, high-resolution mass spectrometry (HRMS) showing two peaks corresponding to the [M + Na] + (m/z = 1291.2774)and to the [M + K] + (m/z = 1307.2502)cations, with the expected isotopic profiles, unambiguously confirmed the formation of ruthenium complex 9.
phine borane 8 was refluxed in methanol [35], and the reaction was monitored by TLC until full conversion, which was observed after 7 h.The formation of deprotected phosphine 8 was confirmed by 31 P NMR analysis carried out on the crude reaction mixture, which showed a shift of the unique signal from 11.3 ppm for 8 to −22.2 pm for 1, in agreement with the value reported for the 1-diphenylphosphinopropan-2-yl acetate (−22 ppm) [36].The ligand (1 equivalent) was then reacted with the dimeric [RuCl2(p-cymene)]2 organometallic precursor (0.5 equivalent) in dichloromethane.After recrystallization, ruthenium complex 9 was isolated in 72% yield.Its 31 P spectrum displayed an important upfield shift from −22.2 ppm in the free ligand to 17.2 ppm for the complex.It is interesting to note that the p-cymene ligand showed in the 13 C NMR spectrum a desymmetrization of its four aromatic CH atoms, which appeared as four signals at 91.25, 89.61, 86.65, and 84.23 ppm.In addition, the two CH3 of the isopropyl group were, in the 1 H NMR spectrum, unusually shielded at 0.71 and 0.90 ppm, compared with the classical chemical shift around 0.90 ppm [37,38].Finally, high-resolution mass spectrometry (HRMS) showing two peaks corresponding to the [M + Na] + (m/z = 1291.2774)and to the [M + K] + (m/z = 1307.2502)cations, with the expected isotopic profiles, unambiguously confirmed the formation of ruthenium complex 9. Scheme 3. Synthesis of ruthenium complex 9.
Ruthenium complex 9 was tested for the asymmetric reduction of acetophenone.The runs were performed using classical conditions [39] using NaOH as the base in isopropanol ( i PrOH) as the solvent and hydrogen source.Three experiments, with 1 mol% of catalyst, were carried out at different temperatures for 1 h (Table 1).At 60°C, a conversion of 60% with an ee of 12% was observed (Table 1, entry 1).Increasing the temperature to 80°C slightly modified the catalytic outcome; the conversion rose to 68% with an ee of 14% (Table 1, entry 2).Conversely, repeating the run at 100°C did not favor the catalytic reaction; the conversion was identical as in the case of 80°C; however, the ee decreased to 4% (Table 1, entry 3).These observed weak enantiomeric excesses were of the same order of magnitude as those generally measured with monodentate ligands [40].These results show that even when calix [4]arene is a sterically hindered substituent, its influence on the transfer of chirality from the ligand to the substrate is relatively low. 1 Reagents and conditions: ruthenium complex 9 (1 mol%), acetophenone (0.10 mmol), NaOH (0.025 mmol), i PrOH (0.125 mL, 1.63 mmol), 1 h.The conversions were determined on the crude reaction mixture by 1 H NMR spectroscopy by integrating the CH3 signals, and the ees were determined by chiral-phase GC.
Ruthenium complex 9 was tested for the asymmetric reduction of acetophenone.The runs were performed using classical conditions [39] using NaOH as the base in isopropanol ( i PrOH) as the solvent and hydrogen source.Three experiments, with 1 mol% of catalyst, were carried out at different temperatures for 1 h (Table 1).At 60 • C, a conversion of 60% with an ee of 12% was observed (Table 1, entry 1).Increasing the temperature to 80 • C slightly modified the catalytic outcome; the conversion rose to 68% with an ee of 14% (Table 1, entry 2).Conversely, repeating the run at 100 • C did not favor the catalytic reaction; the conversion was identical as in the case of 80 • C; however, the ee decreased to 4% (Table 1, entry 3).These observed weak enantiomeric excesses were of the same order of magnitude as those generally measured with monodentate ligands [40].These results show that even when calix [4]arene is a sterically hindered substituent, its influence on the transfer of chirality from the ligand to the substrate is relatively low.until full conversion, which was observed after 7 h.The formation of deprotected phosphine 8 was confirmed by 31 P NMR analysis carried out on the crude reaction mixture, which showed a shift of the unique signal from 11.3 ppm for 8 to −22.2 pm for 1, in agreement with the value reported for the 1-diphenylphosphinopropan-2-yl acetate (−22 ppm) [36].The ligand (1 equivalent) was then reacted with the dimeric [RuCl2(p-cymene)]2 organometallic precursor (0.5 equivalent) in dichloromethane.After recrystallization, ruthenium complex 9 was isolated in 72% yield.Its 31 P spectrum displayed an important upfield shift from −22.2 ppm in the free ligand to 17.2 ppm for the complex.It is interesting to note that the p-cymene ligand showed in the 13 C NMR spectrum a desymmetrization of its four aromatic CH atoms, which appeared as four signals at 91.25, 89.61, 86.65, and 84.23 ppm.In addition, the two CH3 of the isopropyl group were, in the 1 H NMR spectrum, unusually shielded at 0.71 and 0.90 ppm, compared with the classical chemical shift around 0.90 ppm [37,38].Finally, high-resolution mass spectrometry (HRMS) showing two peaks corresponding to the [M + Na] + (m/z = 1291.2774)and to the [M + K] + (m/z = 1307.2502)cations, with the expected isotopic profiles, unambiguously confirmed the formation of ruthenium complex 9. Scheme 3. Synthesis of ruthenium complex 9.
Ruthenium complex 9 was tested for the asymmetric reduction of acetophenone.The runs were performed using classical conditions [39] using NaOH as the base in isopropanol ( i PrOH) as the solvent and hydrogen source.Three experiments, with 1 mol% of catalyst, were carried out at different temperatures for 1 h (Table 1).At 60°C, a conversion of 60% with an ee of 12% was observed (Table 1, entry 1).Increasing the temperature to 80°C slightly modified the catalytic outcome; the conversion rose to 68% with an ee of 14% (Table 1, entry 2).Conversely, repeating the run at 100°C did not favor the catalytic reaction; the conversion was identical as in the case of 80°C; however, the ee decreased to 4% (Table 1, entry 3).These observed weak enantiomeric excesses were of the same order of magnitude as those generally measured with monodentate ligands [40].These results show that even when calix [4]arene is a sterically hindered substituent, its influence on the transfer of chirality from the ligand to the substrate is relatively low. 1 Reagents and conditions: ruthenium complex 9 (1 mol%), acetophenone (0.10 mmol), NaOH (0.025 mmol), i PrOH (0.125 mL, 1.63 mmol), 1 h.The conversions were determined on the crude reaction mixture by 1 H NMR spectroscopy by integrating the CH 3 signals, and the ees were determined by chiral-phase GC.

Materials and Methods
1 H, 13 C{ 1 H} and 31 P{ 1 H} NMR spectra were recorded with the Bruker Avance III spectrometer (500 MHz) (Billerica, MA, USA) in CDCl 3 and were calibrated according to residual protonated solvent (δ = 7.26 ppm and 77.16 ppm for 1 H and 13 C{ 1 H} NMR, respectively). 31P{ 1 H} NMR spectroscopic data were given relative to external H 3 PO 4 .

X-ray Crystal Structure Analysis
Slow diffusion of methanol into a CH 2 Cl 2 solution of calixarene 6 led to the formation of single crystals, which were suitable for X-ray analysis.Analysis was carried out on a Bruker APEX II DUO Kappa-CCD diffractometer equipped with an Oxford Cryosystem liquid N 2 device, using Cu-Kα radiation (λ = 1.54178Å).The crystal detector distance was 40 mm.The cell parameters were determined (APEX3 software [43]) from reflections taken from three sets of six frames, each at 20 s exposure.The structure was solved using the program SHELXT-2018 [44].The refinement and all further calculations were carried out using SHELXL-2018 [45].H-atoms were included in calculated positions and treated as riding atoms using SHELXL default parameters.Non-H atoms were refined anisotropically, using weighted full-matrix least-squares on F 2 .A semi-empirical absorption correction was applied using SADABS in APEX3 [43].Data collection and structure refinement details are given in Table 2. 3.8.General Procedure for Ruthenium-Catalyzed Reduction of Acetophenone A 1 mL vial, under inert atmosphere, was filled with NaOH (1.0 mg, 25 µmol), acetophenone (12 µL, 100 µmol), and a solution of ruthenium complex 9 (1.3 mg, 1 µmol) in i PrOH (0.125 mL, 1.63 mmol, around 16 equiv./ketone).The reaction mixture was heated for 1 h.The solution was diluted with 0.2 mL of CH 2 Cl 2 and passed through a Millipore filter.An aliquot was analyzed by GC with a Chirasil-DEX CB column (25 m × 0.25 mm) (Agilent Technologies, Santa Clara, CA, USA) to determinate the enantiomeric excess.The remaining solution was concentrated under vacuum and the resulting crude solution was analyzed by 1 H NMR spectroscopy to determinate the conversion.
The arene-ruthenium complex, generated from the phosphine precursor and [RuCl 2 (pcymene)] 2 , was tested in the asymmetric reduction of acetophenone.Although sterically congested, the calix [4]arenyl substituent did not allow an effective transfer of chirality from the ligand to the substrate, resulting in a modest enantiomeric excess.
Further work is aimed at exploiting the potential of Evans' oxazolidinone methodology for the synthesis of chiral phosphinated calixarenes and their application as ligands in the asymmetric reduction of olefins.