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Article

How Do Positions of Phosphito Units on a Calix[4]Arene Platform Affect the Enantioselectivity of a Catalytic Reaction?

by
Shaima Hkiri
and
David Sémeril
*
Synthèse Organométallique et Catalyse, UMR-CNRS 7177, Institut de Chimie de Strasbourg, Université de Strasbourg, 4 rue Blaise Pascal, 67008 Strasbourg, France
*
Author to whom correspondence should be addressed.
Organics 2022, 3(4), 470-480; https://doi.org/10.3390/org3040030
Submission received: 13 June 2022 / Revised: 25 August 2022 / Accepted: 12 October 2022 / Published: 9 November 2022
(This article belongs to the Special Issue Progress in Synthesis and Applications of Phosphorus-Containing Compounds)
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Abstract

:
Three chiral diphosphites, (S,S)-5,17-bis(1,1′-binaphthyl-2,2′-dioxyphosphanyloxy)-25,26,27,28-tetrapropyloxycalix[4]arene (1), (S,S)-5,11,17,23-tetra-tert-butyl-25,27-dipropoxy-26,28-bis(1,1′-binaphthyl-2,2′-dioxyphosphanyloxy)calix[4]arene (2) and (S,S)-5,11,17,23-tetra-tert-butyl-25,26-dipropoxy-27,28-bis(1,1′-binaphthyl-2,2′-dioxyphosphanyloxy)calix[4]arene (3), based on conical calix[4]arene were investigated in the rhodium-catalyzed asymmetric hydrogenation of α-dehydroamino esters. High conversions were observed after 24 h under 5 bar of hydrogen whatever the employed diphosphite, and the chiral induction increases in the order 1 < 3 < 2. This may be due to the presence of the calix[4]arene moiety, which by its presence modifies the second coordination sphere of the catalytic center. The larger steric hindrance around the rhodium atom leads to the higher enantiomeric excess.

1. Introduction

Since the rational synthetic methods developed by Gutsche 45 years ago via precise cyclocondensation reactions of para-substituted phenols with formaldehyde [1,2,3,4], calix[4]arene has become a preferred semi-rigid platform for the preparation of convergent ligands [5,6,7,8,9]. Among these, phosphorus-based ligands are often used in transition metal chemistry in particular for catalytic applications [10,11]. The phosphorus atom(s) can be specifically grafted on the upper [12,13,14,15,16,17,18,19,20] or lower [21,22,23,24,25,26,27,28,29,30] rim of the calix[4]arene.
Due to the intrinsic properties of calixarene, its incorporation in the ligand structure presents many advantages such as stabilization of the active species thanks to the steric hindrance generated by the macrocycle [31] or by additional interactions with the auxiliary chains [32,33], increased regioselectivity of the reaction by encapsulation of the catalytic center [34,35], inherent chirality of the calixarene leading to optically active ligands [36,37,38], intrinsic dynamics of the metal center which allow speeding up elementary steps of catalytic cycles [39,40], supramolecular catalysis by trapping the aromatic substrate in its cavity [41], etc. However, the study of the structure–activity relationship is rarely studied; especially from the point of view of academic research, the understanding of the mechanistic aspects needs to be improved. In fact, the position of the phosphorus atom(s) on the calixarenyl platform can drastically affect the coordination sphere of the metal and the catalytic outcome as observed, for example, in the oligomerization of ethylene [42] with tetrahedral [NiX2(diphosphine)] (X = Cl or Br) complexes, namely cis-P,P’-dibromo{5,17-dibromo-11,23-bis(diphenylphosphino)-25,26,27,28-tetrapropyl-oxycalix[4]arene}nickel [43] (A) and cis-P,P’-dichloro-{5,11,17,23-tetra-tert-butyl-25,26-bis(diphenylphosphino-methoxy)-27,28-dihydroxycalix[4]arene}nickel [44] (B) using methylaluminoxane as an activator (Figure 1). While pre-catalyst A led to the formation of butenes, C4–C12 oligomers with a Schulz–Flory distribution (α = 0.22) were obtained when complex B, which has a significantly higher steric hindrance, was employed.
The possibility of fine tuning the coordination sphere of a catalytic center with the calixarenyl preorganization platform allows the modulation of the steric properties of the ligand to a specific reaction. In this context, we now report the use of calixarenyl diphosphites 1–3 for the asymmetric hydrogenation of α-dehydroamino esters (Figure 2). The objective of this work is to relate the positioning of the phophito units on the macrocycle to the efficiency of the chirality transfer from the ligand to the substrates.

2. Materials and Methods

All manipulations were carried out under dry argon. Routine 1H, 13C{1H} and 31P{1H} spectra were recorded with Bruker FT instruments (AC 300 and 400). 1H NMR and 13C{1H} spectra were referenced to residual protonated solvents (δ = 7.16 ppm and 128.08 ppm for C6D6, respectively, and 7.26 ppm and 77.16 ppm for CDCl3, respectively). 31P NMR spectroscopic data are given relative to external H3PO4. Chemical shifts and coupling constants are reported in ppm and Hz, respectively. Mass spectra were recorded on a Bruker MicroTOF spectrometer (ESI-TOF). The catalytic solutions were analyzed by using a Varian 3900 gas chromatograph equipped with a CHROMPAK chiral fused silica Chirasil-L-Val column (25 m × 0.25 mm). (S,S)-5,17-Bis(1,1′-binaphthyl-2,2′-dioxyphosphanyloxy)-25,26,27,28-tetrapropyloxycalix[4]arene (1) [45] and (S,S)-5,11,17,23-tetra-tert-butyl-25,27-dipropoxy-26,28-bis(1,1′-binaphthyl-2,2′-dioxyphosphanyl-oxy)calix[4]arene (2) [46] were prepared by literature procedures.

2.1. Synthesis of 5,11,17,23-Tetra-tert-butyl-25,26-dipropyloxy-27,28-dihydroxycalix[4]arene (4) [47]

First, 15,16,17,18-tetra-tert-butyl-25,26,27,28-tetrahydroxycalix[4]arene (2.500 g, 3.8 mmol) dissolved in DMF (500 mL) at 50 °C was deprotonated with NaH (60% dispersion in oil; 0.770 g, 19.3 mmol). After 0.5 h, nPrBr (1.050 g, 0.78 mL, 8.5 mmol) was added, and the reaction mixture was heated at 60 °C. After 4 days, the solvent was evaporated to dryness, and the solid residue was solubilized in CH2Cl2 (100 mL). The resulting suspension was washed with HCl (2 N, 100 mL). The aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The combined organic layers were dried over MgSO4 and concentrated. The desired white solid product was precipitated by addition of methanol, filtered off and dried under vacuum (1.692 g, 60%). 1H NMR (300 MHz, CDCl3): δ = 8.89 (s, 2H, OH), 7.00 (d, 2H, CH arom, 4J = 2.4 Hz), 6.98 (d, 2H, CH arom, 4J = 2.8 Hz), 6.97 (d, 2H, CH arom, 4J = 2.8 Hz), 6.91 (d, 2H, CH arom, 4J = 2.4 Hz), 4.49 and 3.32 (AB system, 2H, ArCH2Ar, 2J = 12.6 Hz), 4.32 and 3.34 (AB system, 4H, ArCH2Ar, 2J = 12.9 Hz), 4.29 and 3.32 (AB system, 2H, ArCH2Ar, 2J = 13.2 Hz), 4.08–4.00 (m, 2H, OCH2), 3.90–3.82 (m, 2H, OCH2), 2.08 (hex, 4H, CH2CH3, 3J = 7.5 Hz), 1.26 (s, 18H, C(CH3)3), 1.12 (t, 6H, CH2CH3, 3J = 7.5 Hz), 1.10 (s, 18H, C(CH3)3) ppm.

2.2. Synthesis of (S,S)-5,11,17,23-Tetra-tert-butyl-25,26-dipropoxy-27,28-bis(1,1′-binaphthyl-2,2′-dioxyphosphanyloxy)calix[4]arene (3)

Here, 5,11,17,23-tetra-tert-butyl-25,26-dipropyloxy-27,28-dihydroxycalix[4]arene (4) (0.600 g, 0.82 mmol) in refluxing toluene (30 mL) was deprotonated with NaH (60% dispersion in oil, 0.072 g, 1.80 mmol). After 24 h, a solution of [(S)-(1,1′-binaphthalene-2,2′-diyl)]chlorophosphite (0.718 g, 2.05 mmol) in toluene (15 mL) was added at 0 °C. The resulting reaction mixture was stirred at room temperature for an additional 2 h. The crude solution was filtered through Al2O3, which was washed twice with toluene (2 × 15 mL). The desired white solid product 3 was obtained by evaporation of the toluene under reduced pressure (0.792 g, yield 71%). 1H NMR (300 MHz, C6D6): δ = 8.10 (d, 1H, CH arom, 3J = 8.7 Hz), 7.78 (d, 1H, CH arom, 3J = 8.7 Hz), 7.71 (d, 1H, CH arom, 3J = 8.1 Hz), 7.63 (d, 1H, CH arom, 3J = 8.1 Hz), 7.60–7.53 (m, 3H, CH arom), 7.47 (d, 1H, CH arom, 3J = 8.7 Hz), 7.29–7.22 (m, 4H, CH arom), 7.13–7.02 (m, 12H, CH arom), 7.00–6.93 (m, 3H, CH arom), 6.92–6.90 (m, 2H, CH arom), 6.76 (brs, 2H, CH arom), 6.03 (brs, 1H, CH arom), 5.32 and 3.48 (AB system, 2H, ArCH2Ar, 2J = 13.2 Hz), 4.97 and 3.46 (AB system, 2H, ArCH2Ar, 2J = 12.9 Hz), 4.34 and 3.14 (AB system, 2H, ArCH2Ar, 2J = 12.3 Hz), 4.32 and 3.38 (AB system, 2H, ArCH2Ar, 2J = 13.5 Hz), 3.78–3.52 (m, 4H, OCH2), 1.81–1.66 (m, 4H, CH2CH3), 1.45 (s, 9H, C(CH3)3), 1.39 (s, 9H, C(CH3)3), 1.09 (s, 9H, C(CH3)3), 0.99 (s, 9H, C(CH3)3), 0.95 (t, 3H, CH2CH3, 3J = 7.4 Hz), −0.17 (t, 3H, CH2CH3, 3J = 7.5 Hz); 13C{1H} NMR (75 MHz, C6D6): δ = 154.30–122.35 (arom C’s), 78.38 (s, OCH2), 76.28 (s, OCH2), 34.31 (s, C(CH3)3), 34.15 (s, C(CH3)3), 34.01 (s, C(CH3)3), 32.81 (s, ArCH2Ar), 32.61 (s, ArCH2Ar), 32.36 (s, ArCH2Ar), 32.11 (s, C(CH3)3), 31.96 (s, C(CH3)3), 31.55 (s, ArCH2Ar), 31.40 (s, C(CH3)3), 23.62 (s, CH2CH3), 22.90 (s, CH2CH3), 10.92 (s, CH2CH3), 8.84 (s, CH2CH3); 31P{1H} NMR (121 MHz, C6D6): δ = 150.7 (s, OP(OAr)2) ppm. Elemental analysis (%): calcd for C90H90P2O8 (1361.62): C 79.39, H 6.66; found: C 79.16, H 6.84.

2.3. Synthesis of cis-P,P’-{[(S,S)-5,11,17,23-Tetra-tert-butyl-25,27-dipropyloxy-26,28-bis (1,1′-binaphtyl-phosphite)calix[4]arene]-1,5-cyclooctadiene}rhodium(I) Tetrafluoroborate (5)

Ligand 2 (0.284 g, 0.21 mmol) in CH2Cl2 (5 mL) was added drop to drop to a solution of [Rh(cod)2]BF4 (0.077 g, 0.19 mmol) in CH2Cl2 (250 mL). After 16 h, the resulted solution was concentrated to ca. 3 mL, and the complex 5 was precipitated out after the addition of hexane (50 mL). The orange precipitate was filtered off and dried under vacuum (0.280 g, 89% yield). 1H NMR (300 MHz, CDCl3): δ = 8.24 (d, 2H, CH arom, 3J = 8.8 Hz), 8.03 (d, 2H, CH arom, 3J = 8.8 Hz), 7.99 (d, 2H, CH arom, 3J = 8.1 Hz), 7.78 (d, 2H, CH arom, 3J = 8.1 Hz), 7.68 (d, 2H, CH arom, 3J = 8.9 Hz), 7.51–7.35 (m, 6H, CH arom), 7.24–7.10 (m, 4H, CH arom), 6.98 (d, 2H, CH arom, 3J = 8.6 Hz), 6.86 (d, 2H, CH arom, 3J = 8.6 Hz), 6.79 (d, 2H, CH arom, 4J = 2.1 Hz), 6.58 (d, 2H, CH arom, 4J = 2.4 Hz), 6.28 (d, 2H, CH arom, 4J = 2.1 Hz), 6.23 (d, 2H, CH arom, 4J = 2.1 Hz), 6.19–6.09 (m, 2H, CH of cod), 5.01 and 2.98 (AB system, 4H, ArCH2Ar, 2J = 13.5 Hz), 4.89 and 3.31 (AB system, 4H, ArCH2Ar, 2J = 12.7 Hz), 4.46-4.38 (m, 2H, OCH2), 4.36–4.23 (m, 2H, CH of cod), 4.11–3.97 (m, 2H, OCH2), 2.74–2.58 (m, 2H, CH2 of cod), 2.40–2.33 (m, 2H, CH2 of cod), 2.33–2.10 (m, 4H, CH2CH3), 1.65–1.53 (m, 2H, CH2 of cod), 1.16 (t, 6H, CH2CH3, 3J = 7.4 Hz), 1.09–1.04 (m, 2H, CH2 of cod), 1.01 (s, 18H, C(CH3)3), 0.74 (s, 18H, C(CH3)3); 13C{1H} NMR (75 MHz, CDCl3): δ = 151.16–119.71 (arom Cs), 106.66 (s, CH of cod), 95.99 (s, CH of cod), 77.92 (s, OCH2), 34.97 (s, CH2 of cod), 33.69 (s, C(CH3)3), 33.61 (s, CH2 of cod), 33.60 (s, ArCH2Ar), 33.61 (s, CH2 of cod), 33.58 (s, C(CH3)3), 33.36 (s, ArCH2Ar), 31.10 (s, C(CH3)3), 30.90 (s, C(CH3)3), 26.79 (s, CH2 of cod), 23.54 (s, CH2CH3), 10.27 (s, CH2CH3); 31P{1H} NMR (121 MHz, CDCl3): δ = 120.7 (d, OP(OAr)2, 1JP-Rh = 256.8 Hz) ppm. MS (ESI TOF), m/z: 1571.61 [M–BF4]+ and 1463.54 [M–C8H12–BF4]+ expected isotopic profiles. Elemental analysis (%): calcd for C98H102BF4O8P2Rh (1659.51): C 70.93, H 6.19; found: C 70.86, H 5.94.

2.4. General Procedure for the Hydrogenation Experiments

Hydrogenation experiments were carried out in a glass-lined, 100 mL stainless steel autoclave containing a magnetic stirring bar. The reactor was flushed with nitrogen and charged with [Rh(cod)2]BF4 (0.01 mmol), ligand (0.01 mmol) and CH2Cl2 (10 mL). The resulting mixture was stirred at room temperature for 0.5 h. The α-dehydroamino esters (1.00 mmol) were then added. The autoclave was flushed twice with H2, pressurized to 5 bars and stirred at room temperature for 24 h. After depressurization of the reactor, the solution was passed through a short silica column to remove the catalyst. The conversion and the enantioselectivity were determined by 1H NMR spectroscopy and by chiral GC analysis using a CHROMPAK chiral fused silica Chirasil-L-Val column (25 m × 0.25 mm), respectively.
N-Acetyl-phenylalanine methyl ester (7a) 1H NMR (CDCl3, 300 MHz): δ = 7.31–7.21 (m, 3H, CH arom), 7.09 (dd, 2H, CH arom, 3J = 7.7 Hz, 4J = 1.9 Hz), 6.05 (d, 1H, NH, 3J = 7.8 Hz), 4.87 (dt, 1H, CH2CHNH, 3J = 7.8 Hz, 3J = 5.8 Hz), 3.71 (s, 3H, CO2CH3), 3.12 and 3.09 (ABX system, 2H, CH2CH, 2J = 13.8 Hz, 3J = 5.8 Hz), 1.97 (s, 3H, NHCOCH3) ppm.
N-Acetyl-4-fluoro-phenylalanine methyl ester (7b) 1H NMR (CDCl3, 300 MHz): δ = 7.07–6.93 (m, 4H, CH arom), 6.02 (d, 1H, NH, 3J = 7.6 Hz), 4.85 (dt, 1H, CH2CHNH, 3J = 7.6 Hz, 3J = 5.7 Hz), 3.71 (s, 3H, CO2CH3), 3.12 and 3.04 (ABX system, 2H, CH2CH, 2J = 14.1 Hz, 3J = 5.7 Hz), 1.98 (s, 3H, NHCOCH3) ppm.
N-Acetyl-4-chloro-phenylalanine methyl ester (7c) 1H NMR (CDCl3, 300 MHz): δ = 7.23 (d, 2H, CH arom, 3J = 8.3 Hz), 7.01 (d, 2H, CH arom, 3J = 8.3 Hz), 6.18 (brs, 1H, NH), 4.83 (dt, 1H, CH2CHNH, 3J = 7.8 Hz, 3J = 5.8 Hz), 3.69 (s, 3H, CO2CH3), 3.98 and 3.01 (ABX system, 2H, CH2CH, 2J = 13.8 Hz, 3J = 5.8 Hz), 1.95 (s, 3H, NHCOCH3) ppm.
N-Acetyl-3,4-dichloro-phenylalanine methyl ester (7d) 1H NMR (CDCl3, 300 MHz): δ = 7.33 (d, 1H, CH arom, 3J = 8.3 Hz), 7.18 (d, 1H, CH arom, 4J = 2.2 Hz), 6.93 (dd, 1H, CH arom, 3J = 8.3 Hz, 4J = 2.2 Hz), 6.19 (d, 1H, NH, 3J = 7.6 Hz), 4.85 (dt, 1H, CH2CHNH, 3J = 7.6 Hz, 3J = 5.9 Hz), 3.72 (s, 3H, CO2CH3), 3.11 and 2.99 (ABX system, 2H, CH2CH, 2J = 13.9 Hz, 3J = 5.9 Hz), 1.98 (s, 3H, NHCOCH3) ppm.

3. Results

Starting from the 5,11,17,23-tetra-tert-butyl-25,26,27,28-tetrol-calix[4]arene, two diphosphites in which the phosphito units are grafted on distal aromatic either on the upper or on the lower rim of the macrocycle, namely (S,S)-5,17-bis (1,1′-binaphthyl-2,2′-dioxyphosphan-yloxy)-25,26,27,28-tetrapropyloxycalix[4]arene (1) [45] and (S,S)-5,11,17,23-tetra-tert-butyl-25,27-dipropoxy-26,28-bis(1,1′-binaphthyl-2,2′-dioxyphosphanyloxy)calix[4]arene (2) [46] were prepared following previous reports of our group. The third diphosphite was obtained in two steps: firstly, a double alkylation of two proximally phenolic units with NaH and nPrBr in DMF, which led after 4 days at room temperature to the O-dialkylated precursor 4 [47] in 60% yield. In keeping with a Cs-symmetrical structure, its 1H NMR spectrum displays three distinct AB patterns for the diastereotopic ArCH2Ar protons at 4.49/3.32 (2J = 12.6 Hz), 4.32/3.34 (2J = 12.9 Hz), and 4.29/3.32 (2J = 13.2 Hz) ppm integrated for 2, 4 and 2 protons, respectively.
The second step consists of a double deprotonation of intermediate with NaH 4 followed by a reaction with (S)-(1,1′-binaphthalene-2,2′-diyl)chlorophosphite, which led to the diphosphite 3 (Scheme 1). After workup, diphosphite 3 was isolated in 71% yield and was characterized by a singlet peak at 150.7 ppm in its 31P NMR spectrum. As anticipated, the “cone” conformation of the calix[4]arene was inferred from the corresponding 13C NMR spectrum, which shows four signals in the range 32.81–31.55 ppm for the ArCH2Ar groups [48]. Consistent with a C1-symmetrical compound, the 1H NMR spectrum displays four distinct AB patterns for the ArCH2Ar protons at 5.32/3.48 (2J = 13.2 Hz), 4.97/3.46 (2J = 12.9 Hz), 4.34/3.14 (2J = 12.3 Hz) and 4.32/3.38 (2J = 13.5 Hz) ppm (see Supplementary Materials).
The reaction of the lower rim distally substituted diphosphito-calixarene 2 with [Rh(cod)2]BF4 (cod = 1,5-cyclooctadiene) in CH2Cl2 (0.7 mM) gave, after work-up, the complex 5 in 89% yield as an orange solid (Scheme 2). Owing to the large separation between the two coordinated atoms, 12 bonds, the exclusive formation of a P,P-chelate rhodium complex occurred. The structure of the complex was deduced from its mass spectrum, which shows strong peaks corresponding to the [M–BF4]+ and [M–C8H12–BF4]+ cations at m/z = 1571.61 and 1463.54, respectively. NMR spectra are consistent with a C2-symmetrical molecule: a doublet centered at 120.7 ppm (1JP-Rh = 256.8 Hz) and two AB systems for the diastereotopic ArCH2Ar protons at 5.01/2.98 (2J = 13.5 Hz) and 4.89/3.31 (2J = 12.7 Hz) ppm are observed in the corresponding 31P and 1H NMR spectra, respectively (see Supplementary Materials). Note that when the synthesis of complex 5 was performed in lower-dilution conditions (10 mM), the formation of by-products was observed (85% purity). Nevertheless, with this mixture of complexes, Sandoval et al. observed important enantiomeric excesses in the asymmetric hydrogenation of methyl-(Z)-2-(acetamido)acrylate and methyl-(Z)-2-(acetamido)cinnamate [49].
Four different α-dehydroamino esters, namely (Z)-N-acetyl-dehydro-phenylalanine methyl ester (6a), (Z)-N-acetyl-dehydro-4-fluoro-phenylalanine methyl ester (6b), (Z)-N-acetyl-dehydro-4-chloro-phenylalanine methyl ester (6c) and (Z)-N-acetyl-dehydro-3,4-dichloro-phenylalanine methyl ester (6d) were used to assess the performance of diphosphites 1–3 in the rhodium catalyzed asymmetric hydrogenation (Scheme 3).
In the following tests, the catalytic system was in situ generated by mixing an equimolar amount (0.01 mmol, 1 mol %) of [Rh(cod)2]BF4 as metal precursor and ligand (1–3) in CH2Cl2. The resulting solution was stirred at room temperature for 30 min before the addition of the α-dehydroamino ester (6a–d; 1 mmol). The reaction mixture was stirred under 5 bar of hydrogen for an additional 24 h. 1H NMR carried out on the reaction mixtures revealed that using ligands 1–3, the conversion was increased in the order 1 < 2 < 3 (Table 1). As example, under the latter catalytic conditions, (Z)-N-acetyl-dehydro-4-fluoro-phenylalanine methyl ester (6b) was reduced into N-acetyl-4-fluoro-phenylalanine methyl ester (7b) in 83, 92 and 100% conversion when diphosphites 1, 2 and 3 were employed, respectively (Table 1, entries 2, 6 and 11).
The reduced products 7a–d were obtained with modest enantiomeric excesses (ee) 48–57% when diphosphite 1 was employed (Table 1, entries 1–4). Slightly higher ee values, 58–66%, were measured when ligand 3 was used (Table 1, entries 10–13). The more important ee values, higher than 90%, were measured when the calixarenyl diphosphite 2 was associated with the rhodium precursor (Table 1, entries 5–8). Using the latter catalytic system, N-acetyl-4-chloro-phenylalanine methyl ester (7c) and N-acetyl-4-fluoro- phenylalanine methyl ester (7b) were obtained with ee values of 94 and 95%, respectively. Note that under the previous catalytic conditions, repeating the hydrogenation of α-dehydroamino ester 6a with the well-defined [Rh(2)(cod)]BF4 (5) did not change the catalytic outlook; the reduced product 7a was quantitatively formed (ee = 92%) (Table 1, entry 9). No reduction occurred when the dimeric [RhCl(cod)]2 complex was employed as a rhodium source.
It is interesting to note that only a few examples of asymmetric hydrogenation of α-dehydroamino esters using diphosphites derived from optically pure binol were reported. The nature of the bridge linking the two phosphorus atoms has a direct effect on the catalytic outcome. In fact, when D-glucose [50] or N-phenyldiethanolamine [51] were incorporated in the ligand, low ee values, 28–32%, were measured in the hydrogenation of (Z)-N-acetyl-dehydro-phenylalanine methyl ester (6a). In contrast, important enantiomeric excesses, similar to those obtained with our calixarenyl ligand 2, were obtained by Fan et al. using diphosphite-containing metallacrown ether as a ligand [52] and by Xia et al. with a norbornane backbone [53].

4. Discussion

As interfered from Table 1, the nature of the diphosphite has a direct influence on the results of the asymmetric hydrogenation of the α-dehydroamino esters 6a–d; the chiral induction increases in the order 1 < 3 < 2. Based on the mechanism described by Halpern et al. (Scheme 4) [54,55,56], these differences would not come from electronic factors (in each case P(OAr)3 moieties) but from steric factors generated by the bridge between the two phosphorus atoms, i.e., by the calix[4]arene platform.
With the aim of rationalizing the positioning of the phosphito units on the calix[4]arene platform, molecular mechanism calculations using Spartan of [Rh(L)] moieties (L = 1–3), in which the rhodium atom adopts a square-planar coordination geometry, were performed (Figure 3).
Simulation of the rhodium complex involving the ligand whose phosphito units are grafted onto the distal aromatics on the upper rim of the calixarene [Rh(1)] shows that the rhodium atom is located near the entrance of the macrocyclic cavity. This leads to a largely ligand-free coordination sphere, which is an unfavorable situation for an efficient transfer of chirality from the substituents of the phosphorus atoms to the substrate. In the case of the P,P-chelate [Rh(2)] complex, the rhodium atom was confined in a tight chiral molecular pocket made by the two bulky 1,1′-binaphthalene-2,2′-dioxy moieties and the two auxiliary propyl chains of the calixarene. This feature increases the steric pressure on the catalytic center generated by the optically active phosphite units, which leads to a specific approach of the substrate to the metal allowing an excellent chirality transfer to the α-dehydroamino esters. In the case of diphosphite 3 having its phosphorus atoms grafted on two proximally phenolic rings of the calixarene, the rhodium atom mainly adopts an exo-orientation with respect to the macrocycle [57]. The simulations indicate that the rhodium atom lies in a sterically hindered environment created by the two phosphito units and by one methylenic moiety of the calixarene. This constrained, asymmetric environment may be responsible for a better efficient chirality transfer than ligand 1, but it is less efficient when compared to diphosphite 2.
Regarding the kinetics of the hydrogenation reaction, when substrate (Z)-N-acetyl-dehydro-4-fluoro-phenylalanine methyl ester (6b) or (Z)-N-acetyl-dehydro-4-chloro-phenylalanine methyl ester (6c) were employed, the reduction rate increased in the order 1 < 2 < 3. The most efficient diphosphites are those whose Rh(III)-H intermediates adopt distorted structures due to steric constraints generated by the calix[4]arene (OPr auxiliary groups in 2 and ArCH2Ar moiety in 3). This brings the hydride closer to the coordinated olefin or alkyl chain, which promotes both its migration on the olefin and the final reductive elimination step, respectively (Scheme 4).

5. Conclusions

In summary, we have described the synthesis of optically pure diphosphite in which the two phosphorus atoms are grafted on two proximally phenolic rings of a calix[4]arene. The latter compound and two related calixarenyl diphosphites have been employed in the asymmetric hydrogenation of α-dehydroamino esters. With these three ligands, high conversions were observed after 24 h under 5 bar of hydrogen. We have shown that the position of the two phosphito units on the calixarene platform has a determining role in the chirality transfer from the ligand to the substrate and can be directly related to the steric hindrance generated by the second coordination sphere [58] of the ligand, in other words by the calixarenyl skeleton. In fact, the highest enantiomeric excess, 95%, was obtained with diphosphite 2, which was able to encapsulate the catalytic center inside a molecular pocket generated by the naphthyl substituents and the auxiliary side groups. Further studies aim at exploiting the structural diversity offered by the calix[4]arene platform in homogeneous catalysis.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/org3040030/s1, 1H, 13C and 31P NMR spectra of compounds 3–5 and 7a–d are given.

Author Contributions

Conceptualization, D.S.; investigation, S.H.; formal analysis, S.H.; writing—original draft, S.H.; writing—review and editing, D.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Not applicable.

Acknowledgments

We gratefully acknowledge the University of Carthage and the Tunisian Ministry of Higher Education and Scientific Research for the financial support (grant for S.H.).

Conflicts of Interest

The authors declare no conflict of interest.

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Organics 03 00030 g001 550
Figure 1. Nickel complexes A and B for oligomerization of ethylene.
Figure 1. Nickel complexes A and B for oligomerization of ethylene.
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Figure 2. Calixarenyl diphosphites 1–3 employed in the present study.
Figure 2. Calixarenyl diphosphites 1–3 employed in the present study.
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Scheme 1. Synthesis of diphosphites 1–3.
Scheme 1. Synthesis of diphosphites 1–3.
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Scheme 2. Formation of [Rh(2)(cod)]BF4 complex (5).
Scheme 2. Formation of [Rh(2)(cod)]BF4 complex (5).
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Scheme 3. Enantiomeric hydrogenation of α-dehydroamino esters 6a–d.
Scheme 3. Enantiomeric hydrogenation of α-dehydroamino esters 6a–d.
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Scheme 4. Halpern’s mechanism of hydrogenation.
Scheme 4. Halpern’s mechanism of hydrogenation.
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Figure 3. Spartan simulation of [Rh(L)] moieties (L = 1–3) with a rhodium atom (in green) adopting a square-planar coordination geometry.
Figure 3. Spartan simulation of [Rh(L)] moieties (L = 1–3) with a rhodium atom (in green) adopting a square-planar coordination geometry.
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Table
Table 1. Enantiomeric hydrogenation of α-dehydroamino esters 6a–d 1.
Table 1. Enantiomeric hydrogenation of α-dehydroamino esters 6a–d 1.
EntrySubstrate (Ar)LigandConversion (%) 2ee (%) 3
16a(Ar = Ph)110057 (R)
26b(Ar = 4-F-C6H4)18348 (R)
36c(Ar = 4-Cl-C6H4)18657 (R)
46d(Ar = 3,4-Cl2-C6H3)19152 (R)
56a(Ar = Ph)210091 (R)
66b(Ar = 4-F-C6H4)29295 (R)
76c(Ar = 4-Cl-C6H4)29794 (R)
86d(Ar = 3,4-Cl2-C6H3)210090 (R)
9 46a(Ar = Ph)210092 (R)
106a(Ar = Ph)310062 (R)
116b(Ar = 4-F-C6H4)310066 (R)
126c(Ar = 4-Cl-C6H4)310058 (R)
136d(Ar = 3,4-Cl2-C6H3)310063 (R)
1 Reagents and conditions: [Rh(cod)2]BF4 (1 mol %), ligand (1 mol %), CH2Cl2 (12 mL), P(H2) = 5 bar, 25 °C, 24 h; 2 conversions were determined by 1H NMR spectroscopy (see Supplementary Materials); 3 enantiomeric excess were determinated by chiral GC analysis (CHROMPAK, 25 m × 0.25 mm, Chirasil-L-Val); 4 with [Rh(2)(cod)]BF4 (1 mol %).
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Hkiri, S.; Sémeril, D. How Do Positions of Phosphito Units on a Calix[4]Arene Platform Affect the Enantioselectivity of a Catalytic Reaction? Organics 2022, 3, 470-480. https://doi.org/10.3390/org3040030

AMA Style

Hkiri S, Sémeril D. How Do Positions of Phosphito Units on a Calix[4]Arene Platform Affect the Enantioselectivity of a Catalytic Reaction? Organics. 2022; 3(4):470-480. https://doi.org/10.3390/org3040030

Chicago/Turabian Style

Hkiri, Shaima, and David Sémeril. 2022. "How Do Positions of Phosphito Units on a Calix[4]Arene Platform Affect the Enantioselectivity of a Catalytic Reaction?" Organics 3, no. 4: 470-480. https://doi.org/10.3390/org3040030

APA Style

Hkiri, S., & Sémeril, D. (2022). How Do Positions of Phosphito Units on a Calix[4]Arene Platform Affect the Enantioselectivity of a Catalytic Reaction? Organics, 3(4), 470-480. https://doi.org/10.3390/org3040030

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