Access to Enantiomerically Pure P-Chiral 1-Phosphanorbornane Silyl Ethers

Abstract

Sulfur-protected enantiopure P-chiral 1-phosphanorbornane silyl ethers 5a,b are obtained in high yields via the reaction of the hydroxy group of P-chiral 1-phosphanorbornane alcohol 4 with tert-butyldimethylsilyl chloride (TBDMSCl) and triphenylsilyl chloride (TPSCl). The corresponding optically pure silyl ethers 5a,b are purified via crystallization and fully structurally characterized. Desulfurization with excess Raney nickel gives access to bulky monodentate enantiopure phosphorus(III) 1-phosphanorbornane silyl ethers 6a,b which are subsequently applied as ligands in iridium-catalyzed asymmetric hydrogenation of a prochiral ketone and enamide. Better activity and selectivity were observed in the latter case.

1. Introduction

Chiral phosphines play a pivotal role in asymmetric homogeneous catalysis [1,2,3,4,5,6,7,8]. P-stereogenic phosphines, a special class of chiral phosphines, have been well established in catalysis ever since the pioneering work on asymmetric hydrogenation (AH) employing a P-chiral ligand was introduced by Horner et al. [9] and Knowles et al. [10]. The development of the privileged P-chiral ligand (ethane-1,2-diyl)bis[(2-methoxyphenyl)(phenyl)phosphane] (DIPAMP) by Knowles and coworkers [11] led to the first industrial asymmetric hydrogenation in the production of the drug l-3,4-dihydroxyphenylalanine (l-DOPA) used in the treatment of Parkinson’s disease [12] (Figure 1). A few years later, Noyori, another Nobel prize winner, and his group developed the axially chiral phosphine 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) [13] and showed that complexes with ruthenium were effective in asymmetric hydrogenations of a wide range of olefins and carbonyl compounds [14,15,16,17]. Nowadays, AH is considered one of the most important enantioselective syntheses that gives access to many important optically active compounds. Among the widely used metals in such reactions, the iridium-catalyzed hydrogenations have been extensively studied [18,19,20,21,22]. The symmetric Crabtree catalyst [23], the chiral P,N bidentate PHOX ligand developed by Pfaltz et al. [24,25,26] and BIPI ligands by Busacca et al. [27] are key examples of Ir-based catalysts in hydrogenation reactions. The majority of the developed procedures employ bidentate hetero-donor P,X (X = N, O) ligands as they were believed to considerably influence enantioselectivities due to better chirality transfer [28,29,30,31]. Thus, the reluctance to employ monodentate ligands in AH is understandable, especially given the proven history of success with chelate ligands. However, evidence of high enantiomeric excess (ee) values in AH achieved using monodentate ligands has been reported [32,33,34,35]. Despite the success of the published compounds in enantioselective catalysis, industry and academia are still searching for better, more efficient and sustainable catalysts, resulting in a number of new P-chiral compounds being reported regularly [36,37,38].

Phospholes are known to undergo hetero-Diels–Alder (HDA) reactions with various dienophiles to afford P-heterocyclic compounds [39], and recently, we reported the unprecedented phospha-aza-Diels–Alder reaction using an N-sulfonyl α-imino ester to produce 1-phospha-2-azanorbornenes (PANs) [40]. We also showed that the reactive P–N bond of PANs can be cleaved by both achiral and enantiopure nucleophiles to yield racemic 2,3-dihydrophosphole and optically pure 1-alkoxy-2,3-dihydrophosphole derivatives, respectively [40,41]. Moreover, the reduction of PAN with lithium aluminum hydride (LAH) resulted in a seven-membered P-heterocycle [42]. Previously, we reported the first stereoselective HDA reaction between (5R)-(l-menthyloxy)-2(5H)-furanone (MOxF) and 2H-phospholes (Scheme 1) to produce P-chiral 1-phosphanorbornenes (2) [43] as well as P-chiral 7-phosphanorbornenes [44] in high yields. Moreover, the reduction of 1-phosphanorbornenes yields access to 1-phosphanorbornene diol 3. The latter undergoes an intramolecular Michael addition to afford 1-phosphanorbornane alcohol 4, which can be converted into enantiopure 1-phosphanorbornane bromide for subsequent functionalization [45].

Herein, we report the one-step synthesis of enantiomerically pure P-stereogenic 1-phosphanorbornane silyl ethers obtained via reaction of the hydroxy group in 4 with chlorosilanes followed by desulfurization. The application of these ligands in iridium-catalyzed AH of prochiral enamides, namely methyl-(Z)-α-acetamidocinnamate (MAC), was studied. To our knowledge, such ligands have not yet been tested in AH nor any other enantioselective homogeneous catalysis.

2. Results and Discussion

2.1. Synthesis and Characterization of 5a,b

The enantiopure 1-phosphanorbornane alcohol 4 (PNA) is readily prepared in very good yields [45]. The P-chiral 1-phosphanorbornane silyl ethers 5a,b are obtained by reaction of PNA 4 with chlorosilanes in dimethylformamide (DMF) in the presence of base and catalyst (Scheme 2). The formation of silyl ethers is widely exploited for the protection of alcohols, and numerous suitable silylation reagents have been reported [46,47,48,49]. We selected tert-butyldimethylsilyl chloride (TBDMSCl) and triphenylsilyl chloride (TPSCl), as the corresponding bulky siloxy groups provide high stability in acidic and basic media compared to the less sterically demanding trimethylsilyl or triethylsilyl ethers [49,50].

In this kind of established reaction, the choice of catalyst, solvent and base is important. Initially, when CH₂Cl₂ was used as the solvent, the reaction of 4 with TPSCl was much slower compared to DMF as the solvent. This supports the reported evidence of DMF acting as a catalyst itself in silylation reactions of alcohols [51]. Consistent with the classical procedure developed by Corey et al. [52], imidazole was employed as catalyst to afford 5b, while for the reaction with TPSCl, 4-dimethylaminopyridine (DMAP) was used as it was previously reported to be a successful catalyst.

Stirring at 20 °C overnight resulted in full consumption of PNA as confirmed by ³¹P{¹H} NMR spectroscopy (CDCl₃, singlet at 43.4 ppm for 5a and 43.6 ppm for 5b). Thus, this one-step procedure gives access to 5a,b in very good yields under mild conditions. Pure 5a,b were isolated by crystallization; single crystals suitable for X-ray crystallo-graphy (Supplementary Materials, Section S3) were obtained by dissolving 5a,b in a hot ⁱPrOH/n-hexane mixture and cooling to −25 °C for 17 h. High chemical (98%) and optical purity of the UV-active compound 5a were confirmed by HPLC using a chiral column (Supplementary Materials, Figure S13), while the chemical purity of 5b was verified by elemental analysis. High-resolution mass spectrometry (HRMS) showed the presence of the expected ions, namely [5a + H]⁺ (m/z 491.1617), [5a + NH₄]⁺ (m/z 508.1878), and [5a + Na]⁺ (m/z 513.1447) or [5b + H]⁺ (m/z 347.1631) and [5b + Na]⁺ (m/z 369.1451), respectively. The molecular structures of 5a,b were also confirmed by 2D NMR spectroscopy.

The enantiopure compounds crystallize in the triclinic space group P1 with two independent molecules in the unit cell (5a) or in the monoclinic space group P2₁ with Z = 2 (5b), respectively. The phosphorus atom has a distorted tetrahedral environment (Figure 2). The Si–O bond lengths are in the range of 164.1(2) to 165.4(2) pm, which is in agreement with the literature [53,54].

2.2. Desulfurization of Compounds 5a,b

The P-chiral 1-phosphanorbornane silyl ethers 5a,b can be reduced (desulfurized) to the corresponding phosphorus(III) derivatives with excess of freshly activated Raney nickel at room temperature (Scheme 3). No further work up is required after the reaction is finished. Moreover, this method is mild and tolerates many other functional groups guaranteeing selective desulfurization of the phosphorus atom. In contrast, treating 5a,b with the very strong base lithium aluminum hydride (LAH) at 50 °C requires further quenching and has a risk of side reactions. Nevertheless, ³¹P{¹H} NMR spectra (CDCl₃) of the reaction mixtures of 5a and both reducing agents revealed full conversion of the starting material and formation of 6a (singlet at −45.9 ppm). In contrast, 5b can only be reduced cleanly with excess Raney nickel (singlet at −46.3 ppm for 6b in the ³¹P{¹H} NMR spectrum (CDCl₃)), while the reduction of 5b with LAH resulted in formation of side products, which are presumably formed by deprotection of the silyl group. Although the TBDMS and TPS groups are known to be stable in various media, examples of TBDMS ether cleavage by LAH have been reported previously [55,56,57]. Therefore, the reduction of both compounds was carried out with Raney nickel.

The structures of 6a,b were fully confirmed by 2D NMR spectroscopy. However, due to the high oxophilicity of the phosphorus atom, mainly the corresponding oxides were observed by HRMS ([6a + O + H]⁺ (m/z 475.1795), [6a + O + Na]⁺ (m/z 497.1644), [6b + Na]⁺ (m/z 337.1722), [6b + O + Na]⁺ (m/z 353.1668), and [6b + O + K]⁺ (m/z 369.1420)).

3. Catalysis

Bidentate (mixed donor) chiral ligands developed by Pfaltz et al. [58] and Andersson et al. [59] are mostly used in Ir-catalyzed asymmetric hydrogenation of olefins. On the other hand, the use of chiral monodentate phosphines in Ir-catalyzed enantioselective hydrogenation is uncommon. Encouraged by the previous result on an Ir/phosphoramidite catalyst in AH [34], we evaluated the activity of the bulky monodentate P-chiral 1-phosphanorbornane silyl ethers 6a,b in the asymmetric hydrogenation of carbonyl compounds and olefins. No or minor conversion was observed in the asymmetric hydrogenation of acetophenone (S-1) using [Ir(COD)Cl]₂/6a (1 mol%, M:L = 1:3) as catalyst in dichloromethane (Scheme 4). However, up to 20% conversion was obtained with potassium tert-butoxide as base (20 mol%), albeit with formation of racemic 1-phenylethan-1-ol (P-1) (

Table 1. Asymmetric hydrogenation of acetophenone (S-1) employing Ir/6a as catalyst.

Entry	M/L	Conversion	ee
1	1:3	-	-
2 a	1:2	-	-
3 a	1:3	6%	racemate
4 b	1:3	20%	racemate

^a K₂CO₃ (20 mol%); ^b KO^tBu (20 mol%).

).

Then, the catalytic activities of 6a,b in the asymmetric hydrogenation of the functionalized olefin methyl (Z)-2-acetamido-3-phenylacrylate as benchmark substrate was studied. The catalytic experiments were performed by premixing the ligand (6a or 6b) and the iridium complex (Scheme 5). The hydrogenation of S-2 proceeds with 98% conversion using [Ir(COD)Cl]₂/6a (5 mol%, M:L = 1:1) as the catalyst, but with poor enantioselectivity (

Table 2. Asymmetric hydrogenation of methyl (Z)-2-acetamido-3-phenylacrylate (S-2) using Ir/6a or 6b as catalyst.

Entry	Solvent	Conversion	ee
1 a	CH2Cl2	98%	8%
2 b	CH2Cl2	>99%	9%
3 b	MeOH	90%	8%
4 b	THF	50%	-
5 c	CH2Cl2	95%	8%

Reaction conditions: [Ir(COD)Cl]₂/6a (1:2), substrate/catalyst (S/C) = 100, [substrate] = 0.5 mmol, H₂ (50 bar), solvent = dichloromethane, 30 °C, 15 h. ^a 5 mol% catalyst (M:6a = 1:2); ^b 6a (1 mol%); ^c 6b (1 mol%).

, Entry 1). A similar activity was observed when the catalyst loading was decreased to 0.5 mol% (Table 2, Entry 2) in dichloromethane. Changing the solvent to MeOH and THF did not improve the ee, but resulted in lower conversion (Table 2, Entry 3 and 4). The catalytic activity was not affected by altering the silyl substituent from SiPh₃ (6a) to SiMe₂^tBu (6b) (Table 2, Entry 5). Apparently, the bulky silyl group is not in close proximity to the catalytically active iridium center.

4. Conclusions

A highly efficient and facile synthesis of enantiomerically pure sulfur-protected P-stereogenic 1-phosphanorbornane silyl ethers 5a,b via reaction of the alcohol function of 4 with chlorosilanes is described. Moreover, this method can be applied to prepare a variety of compounds with desired electronic and steric effects via the appropriate choice of the corresponding chlorosilane. The phosphorus(III) derivatives 6a,b are readily accessible via desulfurization of 5a,b with excess Raney nickel. The phosphines 6a,b were tested as ligands in the Ir-catalyzed asymmetric hydrogenation of acetophenone and methyl (Z)-2-acetamido-3-phenylacrylate resulting in moderate to high conversions but poor ee. Further studies on different ligand variations based on the chiral phosphanorbornane motif and their application in enantioselective catalysis are underway.

5. Materials

5.1. General Information

All air-sensitive reactions were carried out under dry high purity nitrogen using standard Schlenk techniques. THF was degassed and distilled from potassium. DMF was degassed and dried under activated 4 Å molecular sieves. TBDMSCl and TPSCl were purchased from Carbolution (St. Ingbert, Germany) or Sigma Aldrich (St. Louis, MO, USA), respectively. The NMR spectra were recorded with a Bruker Avance DRX 400 spectrometer (¹H NMR 400.13 MHz, ¹³C NMR 100.63 MHz, ³¹P NMR 161.98 MHz) or a Bruker Fourier 300 spectrometer (¹H NMR 300.23 MHz, ¹³C NMR 75.50 MHz). ¹³C{¹H} NMR spectra were recorded as APT spectra. The assignment of the chemical shifts and configurations was performed using correlation spectroscopy (COSY) and heteronuclear single quantum coherence (HSQC) techniques. Tetramethylsilane (TMS) was used as the internal standard in the ¹H NMR spectra and all other nuclei spectra were referenced to TMS using the Ξ-scale [60]. The numbering scheme of 5a,b and 6a,b is given in the Supplementary Materials. High-resolution mass spectra (HRMS; electrospray ionization (ESI)) were measured using a Bruker Daltonics APEX II FT-ICR spectrometer (Billerica, MA, USA). IR spectra were obtained with an FTIR spectrometer (Nicolet iS5 FTIR by Thermo Scientific, Waltham, MA, USA) in the range of 400–4000 cm⁻¹ in KBr. Column chromatography was performed using silica 60 (0.015–0.040 mm) purchased from Merck (Rahway, NJ, USA). UV light (389 nm) and iodine (saturated atmosphere) were used as staining reagents. The synthesis of the starting material PNA 4 and Raney nickel activation were carried out according to the literature [45].

5.2. Synthesis

5.2.1. Synthesis of 5a

TPSCl (0.38 g, 1.28 mmol) was added to a solution of 4 (0.2 g, 0.86 mmol) and NEt₃ (0.18 mL, 1.28 mmol) in 12 mL DMF at room temperature. Further 20 mg of DMAP (0.017 mmol) was added and the reaction mixture was stirred for 17 h at 20 °C. The mixture was washed with sat. aq. NH₄Cl solution and the separated organic layer was further washed with 5 mL water 3 times. The combined organic phases were dried over MgSO₄. The solvent was removed under reduced pressure to give a white powder. The compound was dissolved in hot ⁱPrOH/n-hexane and then cooled at −25 °C for 17 h. The formed white solid was isolated, washed with 3 mL cold n-hexane 3 times and dried in vacuo to afford 308 mg of 5a as a white powder. Yield: 308 mg (73%). Single crystals of 5a suitable for X-ray crystallographic studies were obtained by dissolving 5a in a hot ⁱPrOH/n-hexane mixture and cooling to −25 °C for 17 h (Supplementary Materials, Figure S14).

• ¹H NMR (400 MHz, CDCl₃): δ 7.61 (m, 5H), 7.50–7.25 (m, 10H), 4.33 (m, 1H, H-5 or H-6a), 4.16–4.01 (m, 2H), 3.94 (dd, J = 9.9, 5.7 Hz, 1H, H-5 or H-6a), 2.67–2.45 (m, 2H), 2.25 (m, 1H, H-6 or H-7 or H-2), 2.00 (m, 1H), 1.92–1.78 (m, 2H), 1.24 (s, 3H, H-3a or H-4a), 1.20 (s, 3H, H-3a or H-4a) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 135.4 (s, C-aryl), 135.2 (s, C-aryl), 133.4 (s, C-aryl quart.), 130.3 (s, C-aryl), 129.8 (s, C-aryl), 128.0 (s, C-aryl), 127.7 (s, C-aryl), 86.3 (s, C-quart.), 66.3 (s), 59.0 (d, J_C,P = 6.1 Hz), 51.3 (d, ²J_C,P = 19.5 Hz, C-quart.), 47.3 (d, ²J_C,P = 2 Hz, C-5), 44.8 (d, ¹J_C,P = 46.7 Hz, C-6), 41.4 (d, ¹J_C,P = 44.8 Hz, C-2 or C-7), 40.3 (d, ¹J_C,P = 51.8 Hz, C-2 or C-7), 23.9 (d, ³J_C,P = 7.2 Hz, C-3a or C-4a), 18.3 (d, ³J_C,P = 15.9 Hz, C-3a or C-4a) ppm; ³¹P{¹H} NMR (162 MHz, CDCl₃): δ 43.4 (s) ppm; HRMS (ESI, MeCN), m/z: found: 491.1617, calculated for [M + H]⁺: 491.1624; found: 508.1878, calc. for [M + NH₄]⁺: 508.1890; found: 513.1447, calc. for [M + Na]⁺: 513.1444; found: 998.3474, calc. for [2M + NH₄]⁺: 998.3441; found: 1003.3032, calc. for [2M + Na]⁺: 1003.2996; IR (KBr, $\tilde{v}$/cm⁻¹): 3067 (w), 2975 (w), 2881 (w), 1588 (w), 1485 (w), 1427 (m), 1381 (w), 1369 (w), 1306 (w), 1250 (w), 1189 (w), 1114 (s), 1077 (s), 1053 (m), 1042 (m), 1012 (m), 996 (m), 958 (m), 928 (w), 881 (m), 862 (w), 841 (w), 800 (m), 775 (m), 738 (m), 709 (s), 697 (s), 675 (m), 619 (m), 609 (w), 582 (w), 506 (s), 481 (s), 448 (m), 435 (m).

5.2.2. Synthesis of 5b

TBDMSCl (0.146 g, 0.97 mmol) was added to a solution of 4 (0.15 g, 0.65 mmol) and NEt₃ (0.135 mL, 0.97 mmol) in 10 mL DMF at room temperature. Further 13 mg of imidazole (0.19 mmol) were added and the reaction mixture was stirred for 17 h at 20 °C. The mixture was washed with sat. aq. NH₄Cl solution and the separated organic layer was further washed with 5 mL water 3 times. The combined organic phases were dried over MgSO₄. The solvent was removed under reduced pressure to give a white powder. The compound was dissolved in hot ⁱPrOH/n-hexane and then cooled at −25 °C for 17 h. The resulting white solid was washed with 3 mL cold n-hexane 3 times and dried in vacuo to afford 154 mg of 5b as a white powder. Yield: 154 mg (69%). Elemental analysis: C₁₆H₃₁O₂PSSi (346.54) calc. C 55.5%, H 9.0%; found C 55.7%, H 9.1%. Single crystals of 5b suitable for X-ray crystallographic studies were obtained by dissolving 5b in a hot ⁱPrOH/n-hexane mixture and cooling to −25 °C for 17 h (Supplementary Materials, Figure S15).

• ¹H NMR (400 MHz, CDCl₃): δ 4.20–4.07 (m, 2H, H-5a/6a), 3.94 (m, 2H, H-5a/6a), 2.62–2.41 (m, 2H, H-5 or H-6), 2.31 (m, 1H, H-5 or H-6), 2.02 (m, 1H, H-2 or H-7), 1.96–1.83 (m, 2H, H-7 or H-2), 1.26 (s, 3H, H-3a or H-4a), 1.20 (s, 3H, H-3a or H-4a), 0.88 (s, 9H, H-9a), 0.09 (s, 6H, H-8) ppm; ¹³C{¹H} NMR (101 MHz, CDCl₃): δ 86.3 (s, C-quart.), 66.2 (s, C-5a), 58.1 (d, ²J_C,P = 5.6 Hz, C-6a), 51.3 (d, ²J_C,P = 19.4 Hz, C-quart.), 47.3 (d, ²J_C,P = 2.3 Hz, C-5), 44.8 (d, ¹J_C,P = 47.0 Hz, C-6), 41.6 (d, ¹J_C,P = 44.8 Hz, C-2 or C-7), 40.3 (d, ¹J_C,P = 51.8 Hz, C-2 or C-7), 25.8 (s, C-9a), 23.9 (d, ³J_C,P = 7.3 Hz, C-3a or C-4a), 18.3 (d, ³J_C,P = 16.0 Hz, C-3a or C-4a), 18.1 (s, C-9), −5.5 (d, J = 6.1 Hz, C-8) ppm; ³¹P{¹H} NMR (162 MHz, CDCl₃) δ 43.6 (s) ppm; HRMS (ESI, MeCN), m/z: found: 347.1631, calc. for [M + H]⁺: 347.1624; found: 369.1451, calc. for [M + Na]⁺: 369.1444; IR (KBr, $\tilde{v}$/cm⁻¹): 2948 (m), 2925 (m), 2877 (m), 2853 (m), 1497 (w), 1468 (w), 1426 (w), 1383 (w), 1360 (w), 1311 (w), 1258 (m), 1245 (m), 1198 (w), 1162 (w), 1122 (m), 1077 (s), 1041 (m), 1029 (m), 1011 (m), 959 (m), 930 (w), 881 (s), 867 (s), 829 (m), 815 (m), 783 (s), 768 (s), 749 (m), 721 (s), 675 (s), 658 (s), 586 (w), 563 (w), 511 (m), 481 (w), 447 (m).

5.2.3. Synthesis of 6a

Compound 5a (200 mg, 0.41 mmol) was added to a suspension of freshly activated Raney nickel in THF (ca. 2 g, excess) and stirred for 17 h at room temperature. The clear solution was filtered and the black solid was washed four times with 5 mL THF each. The solution was concentrated to give 142 mg of 6a as a white solid (76%). Yield: 142 mg (76%).

• ¹H NMR (400 MHz, THF-d₈): δ 7.54–7.44 (m, 3H), 7.39–7.33 (m, 3H), 7.33–7.19 (m, 6H), 7.13 (m, 3H), 3.86 (m, 2H, H-2 or H-7), 3.61–3.51 (m, 2H, H-5a or H-6a), 2.38 (m, 1H, H-6 or H-5), 2.13 (m, 1H, H-5 or H-6), 1.44–1.16 (m, 4H, H-2 or H-7, H-5a or H-6a), 0.99 (s, 3H, H-3a or H-4a), 0.97 (s, 3H, H-3a or H-4a) ppm; ¹³C{¹H} NMR (101 MHz, THF-d₈): δ 135.1 (s, C-aryl), 134.9 (s, C-aryl), 134.2 (s, C-aryl quart.), 129.6 (s, C-aryl), 129.5 (s, C-aryl), 127.5 (s, C-aryl), 127.4 (s, C-aryl), 86.9 (s, C-quart.), 63.7 (s), 62 (d, ¹J_C,P = 14.9 Hz, C-2 or C-7), 47.5 (d, ²J_C,P = 3.3 Hz, C-5), 45.1 (d, ¹J_C,P = 13.5 Hz, C-6), 38 (d, ¹J_C,P = 16.0 Hz, C-2 or C-7), 36.7 (d, J = 6.6 Hz, C-6a or C-5a), 23.7 (s, C-3a or C-4a), 17.5 (s, C-3a or C-4a) ppm; ³¹P{¹H} NMR (162 MHz, C₆D₆): δ −45.6 (s) ppm; HRMS (ESI, MeCN), m/z: found: 475.1795, calc. for [M + O + H]⁺: 475.1863; found: 497.1644, calc for [M + O + Na]⁺: 497.1672.

5.2.4. Synthesis of 6b

Compound 5b (53 mg, 0.153 mmol) was added to a suspension of freshly activated Raney nickel in THF (ca. 0.44 g, excess) and stirred for 17 h at room temperature. The clear solution was filtered and the black solid was washed four times with 2 mL THF each. The solution was concentrated to give 31 mg of 6b as a colorless oil (63%). Yield: 31 mg (63%).

• ¹H NMR (400 MHz, C₆D₆): δ 3.89–3.82 (m, 2H), 3.77–3.67 (m, 2H), 2.34 (m, 1H), 1.95–1.90 (m, 1H), 1.75 (dt, J = 15.4, 3.1 Hz, 1H, H-2 or H-7), 1.43–1.33 (m, 1H), 1.21–1.15 (m, 1H), 1.1 (s, 3H, H-3a or H-4a), 0.91 (s, 9H, H-8a), 0.89 (s, 3H, H-3a or H-4a), 0.29 (s, 6H, H-7) ppm; ¹³C{¹H} NMR (101 MHz, C₆D₆): δ 64.1(s, C-5a), 61.3 (d, J = 15.0 Hz, C-6a), 47.6 (d, ²J_C,P = 3.6 Hz, C-5), 45.2 (d, ¹J_C,P = 12.9 Hz, C-6), 38.52 (d, ¹J_C,P = 15.7 Hz, C-2 or C-7), 37.03 (d, ¹J_C,P = 6.4 Hz, C-2 or C-7), 25.7 (s, C-9a), 24.5 (s, C-3a or C-4a), 18.1 (s, C-3a or C-4a), −5.7 (d, J = 11.6 Hz, C-8) ppm; ³¹P NMR (162 MHz, C₆D₆): δ −45.6 (s) ppm; HRMS (ESI, MeCN), m/z: found: 337.1722, calc. for [M + Na]⁺: 337.1723; found: 353.1668, calc. for [M + O + Na]⁺: 353.1672; found: 369.1420, calc. for [M + O + K]⁺: 369.1412.

5.3. Catalysis

General Procedure for Hydrogenations

Ketone hydrogenation: The hydrogenation experiments were performed in stainless steel autoclaves charged with an insert suitable for up to 8 reaction vessels (4 mL) with teflon mini stirring bars. In a typical experiment, a reaction vessel was charged with [Ir(COD)Cl]₂ (1 mol%), ligand (1–3 mol%, as desired) and base (20 mol%) and stirred for 10–15 min in the dichloromethane (2 mL). Then, acetophenone (S-1, 0.5 mmol) was added to the reaction vials maintaining the inert atmosphere and the vessels were placed in a high pressure autoclave. The autoclave was purged two times with nitrogen and three times with hydrogen. Finally, it was pressurized at 50 bar H₂ at 25 °C for 12 h. Afterwards, the autoclave was depressurized and the contents of the reaction vessels were diluted with EtOAc and filtered through a short pad of silica. The conversion was determined by GC, GC-MS and NMR measurement and the enantiomeric excess was measured by chiral GC analysis.

Olefin hydrogenation: The hydrogenation experiments were performed in stainless steel autoclaves charged with an insert suitable for up to 8 reaction vessels (4 mL) with teflon mini stirring bars. In a typical experiment, a reaction vessel was charged with [Ir(COD)Cl]₂ (0.5 mol%), ligand (1 mol%) in the appropriate solvent (2 mL). Then, methyl (Z)-2-acetamido-3-phenylacrylate (S-2, 0.5 mmol) was added to the reaction vials maintaining the inert atmosphere and the vessels were placed in a high pressure autoclave. The autoclave was purged two times with nitrogen and three times with hydrogen gas. Finally, it was pressurized at 50 bar H₂ at 30 °C for 15 h. Afterwards, the autoclave was depressurized and the contents of the reaction vessels were diluted with EtOAc and filtered through a short pad of silica. The conversion was determined by GC, GC-MS and NMR measurements and the enantiomeric excess was measured by chiral GC analysis.

5.4. X-ray Crystallography Data

The data were collected on a Gemini diffractometer (Rigaku Oxford Diffraction) using Mo-Kα radiation and ω-scan rotation. Data reduction was performed with CrysAlisPro [61] including the program SCALE3 ABSPACK for empirical absorption correction. All structures were solved by dual space methods with SHELXT [62] and the refinement was performed with SHELXL [63]. For 5b, hydrogen atoms were calculated on idealized positions using the riding model, whereas for 5a, a difference-density Fourier map was used to locate hydrogen atoms. Structure figures were generated with DIAMOND-4 [64].

CCDC deposition numbers 2287331 for 5a and 2287332 for 5b contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/, accessed on 25 May 2023 (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44)1223-336-033 or [email protected]).