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Synthesis 2013; 45(4): 527-535
DOI: 10.1055/s-0032-1316847
paper
© Georg Thieme Verlag Stuttgart · New York

A Scalable Synthesis of Chiral Modular Phosphine–Phosphite Ligands

Mehmet Dindaroğlu
,
Anna Falk
,
Hans-Günther Schmalz*
Further Information

Publication History

Received: 17 October 2012

Accepted after revision: 24 December 2012

Publication Date:
18 January 2013 (online)

 
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Abstract

The outstanding usefulness of phenol-derived chiral phosphine–phosphite ligands has recently been shown in a number of transition-metal-catalyzed C–C bond-forming reactions. This is exemplified by the synthesis of five new ligands in an optimized procedure that can be reliably performed on a multigram scale.


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Key words

Chiral P,P-ligands - enantioselective catalysis - bromine–lithium exchange - synthetic methods - asymmetric 1,4-addition

In the past decades, asymmetric transition-metal catalysis has evolved as an invaluable tool for the stereoselective synthesis of natural products and other high-value compounds such as pharmaceuticals, crop-protection agents, fragrances and fine chemicals.[ 2 ] An important part of this remarkable success story was the development of powerful chiral diphosphine ligands such as BINAP[ 3 ] or ferrocene-based ligands (e.g., Josiphos and Taniaphos).[ 4 ] While the ligands mentioned above and other ‘privileged’ ligand classes have proven their potential in a variety of processes, the identification of a suitable chiral ligand for a given chirogenic metal-catalyzed transformation is still a rather difficult task in many cases. As it is usually not possible to design optimal catalysts from first principles, the screening of ligand libraries is the most promising approach.[ 5 ]

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Figure 1 General architecture of modular phosphine–phosphite ligands (L*) derived from chiral diols

In this context, modular ligand architectures that allow diversity-oriented synthesis of whole libraries (as well as a structural optimization of promising candidates) are of particular value.

In recent years, phosphine–phosphites and phosphine–phosphinites, i.e., unsymmetrical P,P-ligands with electronically different phosphorus ‘teeth’, have received increasing recognition.[ 6 ] In this context, our group introduced modular chiral phosphine–phosphite ligands of type L* with a phenol backbone (Figure [1]).[ 7 ]

These ligands are accessible in only four steps (Scheme [1]) starting from substituted phenols (1). After ortho-bromination of the phenol (→2), the phosphanyl group is introduced by primary O-phosphanylation and protected by addition of BH3 (→3). BuLi-induced lithiation then triggers migration of the phosphanyl group to afford an air-stable intermediate 4 after aqueous workup.[ 8 ] The phosphite moiety is finally established by base-assisted reaction of the phenol function with PCl3 and a chiral diol.

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Scheme 1 General scheme for the synthesis of chiral phosphine–phosphite ligands of type L*

Following this general approach, various ligands were prepared by employing Taddol[ 9 ] (type A), Binol[ 10 ] (type B) or other chiral diols (Figure [1]).[ 11 ] Screening of the resulting ligand library then led to the identification of some (mainly Taddol-derived) ligands that performed extremely well in a range of transition-metal-catalyzed reactions.[7b] [12]

Particularly noteworthy results were obtained in some C–C bond-forming transformations (Scheme [2]). For instance, the enantioselectivities (and the substrate scope) observed for Cu-catalyzed 1,4-addition[ 13 ] and allylic substitution[ 14 ] reactions of Grignard reagents are among the best ever reported for such processes.[ 15 ] Excellent results were also obtained in Rh-catalyzed hydroformylation[ 16 ] and intramolecular [4+2]-cycloaddition[ 17 ] reactions. Moreover, the phenyl-substituted ligand L*-A2 (‘SchmalzPhos’) allowed the Co-catalyzed 1,4-hydrovinylation of dienes to be performed with outstanding levels of regioselectivity.[ 18 ]

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Scheme 2 Performance of ligands of type L*-A in selected C–C bond-forming reactions

Because of the remarkable success of our ligands, we decided to further investigate their potential in other, more challenging transition-metal-catalyzed transformations and also to use them for larger scale applications in natural product synthesis. In this context, we recognized that the described synthesis and purification procedures were not easily reproduced (especially on a multigram scale) in part due to the variable quality of the commercial reagents used. For this reason, we carefully reinvestigated all steps of the synthesis. As a result of this study, we herein present an improved, more reliable and scalable protocol for the synthesis of phosphine–phosphite ligands of type L*. As examples, the preparation of five new ligands (L*-A4–7, and L*-B1; see Figure [2]) is described in detail.

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Figure 2 New ligands described herein

In all cases, the ligand synthesis (Scheme [1]) started from substituted phenol 1, which was ortho-brominated using N-bromosuccinimide (NBS) in the presence of small amounts of N,N-diisopropylamine (DIPA).[ 19 ] To suppress the formation of dibrominated by-products and to circumvent the low solubility of NBS in dichloromethane, a Soxhlet apparatus was used to continuously extract the NBS from the thimble into the reaction mixture. This reaction can be carried out under air but the diisopropyl amine, which is added in catalytic amounts, should be distilled before use. The resulting bromophenol 2 was then converted into the borane-protected phosphinite 3 by reaction with chlorodiphenylphosphine in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) in dichloromethane and subsequent addition of BH3·THF. The yield of this reaction, which is performed under an inert atmosphere, was found to be highly dependent on the quality of the BH3·THF used. Fresh bottles are recommended, and the solutions should be handled strictly under argon to avoid unwanted side-reactions catalyzed by hydride ions. Furthermore, chlorodiphenylphosphine should be distilled and stored carefully under argon to guarantee high yields. The phosphinite 3 was then converted into borane-protected phosphine 4 by treatment with an excess of n-BuLi (1.5 equiv). The reaction proceeds through a lithiated intermediate, which rearranges in an anionic Fries-type process (Scheme [3]).[ 20 ] It should be noted that dibrominated side-products of type 3′ (which always contaminate the brominated phosphinites derived from 2-substituted phenols) are converted into the same product 4, which is always obtained in very pure form. This can be regarded as a ‘self-purification’ process resulting from ‘non-productive’ Br/Li exchange at C4 followed by protonation during work-up (Scheme [3]). Both the borane-protected phosphinites 3 and the corresponding phosphines 4 proved to be air-stable and were obtained, in most cases, as colorless crystalline compounds.

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Scheme 3 Conversion of dibrominated by-products 3′ into the desired intermediates 4 in a ‘self-purification’ process
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Scheme 4 Multigram synthesis of ligands L*-A4–7 and L*-B1

In the last step of the synthesis (Scheme [1] and Scheme [4]) the P-protected ortho-phosphanylphenol 4 was first reacted with PCl3 in dichloromethane at room temperature in the presence of an excess of DABCO, which serves both as a base and as a nucleophile (to take over the BH3 group) and should be sublimed before use. The resulting dichlorophosphite intermediate was then converted into the corresponding phosphine–phosphite ligand by reaction with a chiral diol (which should be thoroughly dried before use). It is noteworthy that, in contrast to L*-A1 and L*-A3–7, ligands with less bulky substituents in the 2-position tend to (partly) decompose during the final chromatographic purification when the solvent or the silica used contains acidic impurities. In such cases, the use of ultra-pure silica[ 21 ] and the replacement of dichloromethane by ethyl acetate are recommended. The overall scheme for the synthesis of the four new ligands L*-A4, L*-A5, L*-A6, L*-A7 and L*-B1 (performed on a multigram scale) is shown in Scheme [4]. Details are given in the experimental section.

The usefulness of the new ligand L*-A4 was demonstrated in the Cu-catalyzed 1,4-addition of ethylmagnesium bromide to cyclohexenone (7) under the established conditions using 2-methyltetrahydrofuran (2-Me-THF) as solvent.[ 13a ] Much to our satisfaction, product 8 was formed with an enantioselectivity of 96% ee, which is the highest value ever observed in this particular (benchmark) reaction (Scheme [5]).

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Scheme 5 Cu-catalyzed enantioselective 1,4-addition of Et-MgBr to cyclohexenone in the presence of ligand L*-A4

In conclusion, we have elaborated an optimized synthetic protocol for the preparation of chiral phosphine–phosphite ligands (L*) starting from readily available substituted phenols. The usefulness of the methodology was demonstrated in a multigram synthesis of five new ligands, one of which exhibited unsurpassed performance in the Cu-catalyzed 1,4-addition reaction of a Grignard reagent. The modular architecture and the short (four-step) synthesis allows facile access to a large variety of chiral ligands (in both enantiomeric forms). Thus, we are confident that this work will contribute to the future application of this ligand class, both in academic research and in process development.

1H, 13C, 31P and 11B NMR spectra were recorded at r.t. in CDCl3 with Bruker instruments (Avance DPX300 or Avance AV300). Chemical shifts (δ) are reported in parts per million (ppm) from tetramethylsilane using the residual solvent resonance as internal standard (CDCl3: δ = 7.24 ppm for 1H NMR; δ = 77.0 ppm for 13C NMR). Multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Coupling constants (J) are presented as absolute values in Hz. IR spectra were recorded at r.t. with a Perkin–Elmer Paragon 1000 FTIR spectrometer in ATR mode. Mass spectra were recorded with Finnigan instruments [MAT Incos 50 galaxy system (for EI) and MAT 900 (for ESI)]. GC-MS were recorded with an Agilent GC 6890N gas chromatograph with a Hewlett Packard 5973N mass-selective detector. Optical rotations were determined with a Perkin–Elmer 343 polarimeter, concentrations (c) are given in g/100 mL. Melting points were determined with a Büchi B-545 instrument. Analytical TLC was carried out using precoated silica gel plates (Merck TLC plates, silica gel 60-F254). Flash column chromatography was performed using Merck silica gel 60 (40–63 μm).

NBS was purchased from Aldrich (>99%) and used as received. Substituted phenols were purchased from TCI (>98.0%) and used as received. DIPA was purchased from Acros, distilled before use, and stored under argon. DABCO was purchased from Alfa Aesar (98%) and purified by sublimation (50 °C, 0.06 mmHg) before use. Chlorodiphenylphosphine (ClPPh2) was purchased from Alfa Aesar (97%) and purified by fractional distillation (160 °C, 0.06 mmHg) before use and stored under argon. BH3·THF (1 M in THF), phosphorus trichloride (PCl3; 2 M in CH2Cl2) and n-butyllithium (1.6 M in hexane) were purchased from Acros and used as received. (R,R)-TADDOL was prepared according to Seebach et al.[ 9 ] and should be anhydrous. (S)-BINOL was purchased from RCA (>99%) and used as received. All moisture-sensitive reactions were carried out in flame-dried glassware under an argon atmosphere. THF was distilled from sodium/benzophenone under argon; CH2Cl2 was heated at reflux and distilled from CaH2 under argon.


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2-Bromo-4,6-di-tert-pentylphenol (2a); Typical Procedure A

A 500 mL round-bottom flask was equipped with a Soxhlet extractor and a reflux condenser with a drying tube. The Soxhlet extractor (30 × 120 mm) was fitted with an extraction thimble (22 × 80 mm), which was filled with NBS (16.50 g, 92.73 mmol, 1.1 equiv). The flask was charged with 2,4-di-tert-pentylphenol (1a; 19.75 g, 84.3 mmol, 1.0 equiv), which was dissolved in CH2Cl2 (250 mL) before DIPA (1.2 mL, 0.85 g, 8.43 mmol, 0.1 equiv) was added. The solution was then heated to reflux for 16 h. After cooling to r.t., the mixture was treated with 2 M H2SO4 (250 mL), transferred into a separatory funnel, and the organic layer was collected. The aqueous layer was extracted with MTBE (3 × 100 mL) and the combined organic layers were washed with brine (300 mL), dried over MgSO4 and filtered. Removal of solvent under reduced pressure on a rotary evaporator afforded the crude product as a yellow to red oil. The oil was purified by flash column chromatography on silica gel (cyclohexane) and the solvent was removed in vacuo to give 2a.

Yield: 24.56 g (93%); light-yellow oil; Rf = 0.65 (cyclohexane).

IR (neat): 3506, 2966, 2866, 1726, 1593, 1566, 1466, 1400, 1373, 1360, 1333, 1296, 1270, 1246, 1170, 1126, 1090, 1056, 1003, 936, 913, 890, 863, 826, 813, 776, 740, 700 cm–1.

1H NMR (300 MHz, CDCl3): δ = 7.25 (s, 1 H, H-3), 7.10 (s, 1 H, H-5), 5.60 (s, 1 H, OH), 1.85 (q, J = 7.5 Hz, 2 H, CH 2CH3), 1.58 (q, J = 7.4 Hz, 2 H, CH 2CH3), 1.35 [s, 6 H, C(CH3)2], 1.23 [s, 6 H, C(CH3)2], 0.69–0.61 (m, 6 H, 2 × CH2CH 3).

13C NMR (APT, 75 MHz, CDCl3): δ = 147.8 (C1), 141.8 (C4), 134.9 (C6), 126.9 (C3), 125.7 (C5), 111.8 (C2), 39.1 (Cq), 37.6 (Cq), 36.9 (CH2CH3), 32.8 (CH2CH3), 28.5 [C(CH3)2], 27.5 [C(CH3)2], 9.4 (CH2 CH3), 9.1 (CH2 CH3).

GC-MS: m/z = 314 (8) [M]+, 312 (8) [M]+, 285 (95), 283 (100), 257 (8), 255 (8), 241 (4), 239 (4), 205 (6), 131 (5), 115 (6), 91 (5), 71 (9), 43 (10).

HRMS (EI, 70 eV): m/z calcd for C16H25BrO: 312.1089; found: 312.109.


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2-Bromo-6-tert-pentylphenol (2b)

Following the same protocol described for 2a, 2-tert-pentylphenol (1b; 16.42 g, 0.1 mol) was reacted with NBS (19.58 g, 0.11 mol) and DIPA (1.4 mL, 1.01 g, 0.01 mol) in CH2Cl2 (250 mL). The crude product was purified by flash column chromatography (cyclohexane–EtOAc, 50:1) to afford 2b.

Yield: 21.88 g (0.09 mmol, 90%); colorless oil; Rf = 0.85 (cyclohexane–EtOAc, 20:1).

IR (neat): 3499, 2960, 2866, 1592, 1430, 1380, 1332, 1266, 1241, 1182, 1141, 1089, 843, 769, 734 cm–1.

1H NMR (300 MHz, CDCl3): δ = 7.33 (dd, J = 8.0, 1.5 Hz, 1 H, H-3), 7.15 (dd, J = 7.9, 1.2 Hz, 1 H, H-5), 6.73 (t, J = 7.9 Hz, 1 H, H-4), 5.76 (s, 1 H, OH), 1.87 (q, J = 7.5, Hz, 2 H, CH 2CH3), 1.35 [s, 6 H, C(CH3)2], 0.64 (t, J = 7.5 Hz, 3 H, CH2CH 3).

13C NMR (APT, 75 MHz, CDCl3): δ = 150.3 (C1), 136.0 (C6), 129.6 (C3), 127.9 (C5), 120.8 (C4), 112.1 (C2), 39.0 (Cq), 32.7 (CH2CH3), 27.5 [C(CH3)2], 9.5 (CH2 CH3).

GC-MS: m/z = 244 (32) [M]+, 242 (32) [M]+, 213 (100), 185 (100), 134 (57), 115 (32), 77 (29), 51 (15).

HRMS (EI, 70 eV): m/z calcd for C11H15BrO: 242.0306; found: 242.031.


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2-Bromo-3-methyl-6-isopropylphenol (2c)

Following the same protocol described for 2a, thymol (1c; 10.0 g, 66.57 mmol) was reacted with NBS (13.03 g, 73.23 mmol) and DIPA (0.94 mL, 0.67 g, 6.66 mmol) in CH2Cl2 (200 mL). The crude product was purified by flash column chromatography (cyclohexane–EtOAc, 60:1) to afford 2c.

Yield: 14.09 g (61.49 mmol, 92%); colorless oil; Rf = 0.38 (cyclohexane).

IR (neat): 3503, 3066, 3026, 2958, 2922, 2868, 1870, 1733, 1605, 1490, 1450, 1405, 1379, 1361, 1343, 1315, 1265, 1209, 1177, 1152, 1132, 1113, 1062, 1030, 954, 892, 804, 781, 743, 720, 705 cm–1.

1H NMR (300 MHz, CDCl3): δ = 7.03 (d, J = 7.8 Hz, 1 H, H-5), 6.77 (d, J = 7.8 Hz, 1 H, H-4), 5.68 (s, 1 H, OH), 3.29 [dt, J = 13.8, 6.9 Hz, 1 H, CH(CH3)2], 2.35 (s, 3 H, CH3), 1.23 [d, J = 6.9 Hz, 6 H, (CH3)2].

13C NMR (APT, 75 MHz, CDCl3): δ = 149.3 (C1), 135.4 (C3), 133.2 (C6), 124.9 (C5), 122.0 (C4), 113.6 (C2), 27.9 [CH(CH3)2], 22.9 (CH3), 22.5 [CH(CH3)2].

GC-MS: m/z = 230 (<5) [M]+, 228 (<5) [M]+, 215 (4), 213 (4), 134 (17), 115 (18), 105 (21), 91 (43), 77 (62), 62 (38), 51 (58), 39 (100).

HRMS (EI, 70 eV): m/z calcd for C10H13BrO: 228.0150; found: 228.015.


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2-Bromo-6-ethylphenol (2d)

Following the same protocol described for 2a, 2-ethylphenol (1d; 10.0 g, 82.0 mmol) was reacted with NBS (16.0 g, 90.2 mmol) and DIPA (1.2 mL, 0.8 g, 8.2 mmol) in CH2Cl2 (250 mL). The crude product was purified by flash column chromatography (cyclohexane) to afford 2d.

Yield: 14.8 g (73.6 mmol, 90%); colorless oil; Rf = 0.55 (cyclohexane–EtOAc, 100:1).

IR (neat): 3508, 2964, 2872, 1597, 1448, 1324, 1232, 1211, 1120, 969, 836, 765, 731, 680 cm–1.

1H NMR (300 MHz, CDCl3): δ = 7.29 (dd, J = 8.0, 1.2 Hz, 1 H, H-3), 7.08 (dd, J = 7.4, 0.6 Hz, 1 H, H-5), 6.74 (t, J = 7.8 Hz, 1 H, H-4), 5.53 (s, 1 H, OH), 2.69 (q, J = 7.5 Hz, 2 H, CH2), 1.22 (t, J = 7.5 Hz, 3 H, CH3).

13C NMR (APT, 75 MHz, CDCl3): δ = 150.0 (C1), 131.9 (C6), 129.3 (C3), 128.7 (C5), 121.4 (C4), 110.4 (C2), 23.9 (CH2), 13.9 (CH3).

GC-MS: m/z = 202 (65) [M]+, 200 (65) [M]+, 187 (100), 185 (100), 121 (73), 107 (31), 91 (43), 77 (84).

HRMS (EI, 70 eV): m/z calcd for C8H9BrO: 199.9837; found: 199.984.


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(2-Bromo-4,6-di-tert-pentylphenoxy)diphenylphosphine Borane Complex (3a); Typical Procedure B

A 500 mL Schlenk flask was charged with 2-bromo-4,6-di-tert-pentylphenol (2a; 23.49 g, 75 mmol, 1.0 equiv), DABCO (10.09 g, 90 mmol, 1.2 equiv) and CH2Cl2 (150 mL) under argon. The resulting solution was stirred for 15 min at r.t., cooled to 0 °C, and ClPPh2 (16.15 mL, 19.86 g, 90 mmol, 1.2 equiv) was added dropwise by using a syringe over a period of 30 min. The resulting white suspension was stirred for 10 min at this temperature, then allowed to warm to r.t. and stirred for 2 h. The reaction mixture was cooled to 0 °C again and a solution of BH3·THF (1 M, 150 mL, 150 mmol, 2.0 equiv) was added by using a syringe. The suspension was stirred for 10 min at 0 °C, then allowed to warm to r.t. and stirred for 1 h. The reaction mixture was quenched with deionized H2O (500 mL), the organic layer was separated and the aqueous layer was extracted with MTBE (3 × 150 mL). The combined organic layers were washed with brine (500 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Column chromatographic purification of the crude product on silica gel (cyclohexane–EtOAc, 50:1) afforded 3a.

Yield: 35.30 g (92%); white solid; mp 134–137 °C; Rf = 0.66 (cyclohexane–EtOAc, 50:1).

IR (neat): 3046, 2961, 2880, 2426, 2386, 2346, 2240, 1590, 1550, 1453, 1434, 1393, 1376, 1360, 1326, 1300, 1260, 1214, 1186, 1106, 1085, 1053, 1030, 996, 903, 863, 823, 786, 726, 690 cm–1.

1H NMR (300 MHz, CDCl3): δ = 8.04–7.97 (m, 4 H, ArH), 7.47–7.38 (m, 6 H, ArH), 7.32 (d, J = 2.3 Hz, 1 H, H-3), 7.16 (br s, 1 H, H-5), 1.57 (q, J = 7.4 Hz, 2 H, CH 2CH3), 1.33 (q, J = 7.4 Hz, 2 H, CH 2CH3), 1.22 [s, 6 H, C(CH3)2], 1.11 [s, 6 H, C(CH3)2], 0.66 (t, J = 7.4 Hz, 3 H, CH2CH 3), 0.48 (t, J = 7.4 Hz, 3 H, CH2CH 3).

13C NMR (APT, 75 MHz, CDCl3): δ = 147.5 (d, J = 5.7 Hz, C1), 146.2 (C4), 141.9 (d, J = 3.0 Hz, C6), 134.3 (d, J = 65.5 Hz, CqAr), 131.3 (CHAr), 131.27 (d, J = 11.2 Hz, CHAr), 129.8 (C3), 128.3 (d, J = 10.8 Hz, CHAr), 125.7 (C5), 116.8 (d, J = 2.4 Hz, C2), 38.8 (Cq), 37.6 (Cq), 36.8 (CH2CH3), 33.3 (CH2CH3), 28.2 [C(CH3)2], 27.9 [C(CH3)2], 9.0 (2 × CH2 CH3).

31P NMR {1H}(121 MHz, CDCl3): δ = 108.1 (d, J = 72.6 Hz, O-PR2).

11B NMR {1H} (96 MHz, CDCl3): δ = –124.2 (br s, BH3).

GC-MS: m/z = 497 (1) [M-BH3]+, 429 (15), 417 (23), 359 (25), 201 (13), 186 (100), 152 (10), 128 (7), 115 (11), 108 (72), 89 (13), 71 (49), 55 (16).

HRMS (EI, 70 eV): m/z [M – BH3]+ calcd for C28H34BrOP: 496.1530; found: 496.151.


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(2-Bromo-6-tert-pentylphenoxy)diphenylphosphine Borane Complex (3b)

Following the same protocol described for 3a, bromophenol 2b (21.5 g, 88.4 mmol) was reacted with DABCO (11.9 g, 106.1 mmol), ClPPh2 (19.0 mL, 23.4 g, 106.1 mmol) and BH3·THF (176.8 mL, 176.8 mmol) in CH2Cl2 (150 mL). The crude product was purified by flash column chromatography (cyclohexane–EtOAc, 50:1) to afford 3b.

Yield: 35.5 g (80.5 mmol, 91%); white solid; mp 121 °C; Rf = 0.60 (cyclohexane–EtOAc, 50:1).

IR (neat): 3056, 2961, 2929, 2873, 2429, 2388, 2348, 1482, 1454, 1437, 1414, 1386, 1377, 1204, 1108, 1087, 1057, 998, 891, 838, 755, 734, 694 cm–1.

1H NMR (300 MHz, CDCl3): δ = 8.03–7.99 (m, 4 H, ArH), 7.47–7.43 (m, 6 H, ArH), 7.40 (dd, J = 7.8, 1.6 Hz, 1 H, ArH), 7.23 (d, J = 7.9 Hz, 1 H, ArH), 6.93 (t, J = 7.9 Hz, 1 H, ArH), 1.34 (q, J = 7.4 Hz, 2 H, CH 2CH3), 1.10 [s, 6 H, C(CH3)2], 0.48 (t, J = 7.4 Hz, 3 H, CH2CH 3).

13C NMR (APT, 75 MHz, CDCl3): δ = 150.1 (d, J = 5.6 Hz, C1), 143.3 (d, J = 3.5 Hz, CqAr), 134.2 (d, J = 65.4 Hz, CqAr), 132.4 (d, J = 1.2 Hz, CHAr), 131.5 (d, J = 2.5 Hz, CHAr), 131.3 (d, J = 11.4 Hz, CHAr), 128.4 (d, J = 10.9 Hz, CHAr), 127.9 (d, J = 0.8 Hz, CHAr), 125.4 (d, J = 1.4 Hz, CHAr), 117.5 (d, J = 3.1 Hz, C2), 38.8 (Cq), 33.3 (CH2CH3), 27.9 [C(CH3)2], 9.0 (CH2 CH3).

31P NMR {1H}(121 MHz, CDCl3): δ = 109.0 (d, J = 71.4 Hz, O-PR2).

11B NMR {1H} (96 MHz, CDCl3): δ = –124.4 (br s, BH3).

GC-MS: m/z = 426 (43) [M – BH3]+, 347 (14), 316 (10), 213 (10), 183 (100), 152 (19), 132 (12), 107 (21), 77 (52), 43 (81).

HRMS (EI, 70 eV): m/z [M – BH3]+ calcd for C23H24BrOP: 426.0748; found: 426.074.


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(2-Bromo-3-methyl-6-isopropylphenoxy)diphenylphosphine Borane Complex (3c)

Following the same protocol described for 3a, bromophenol 2c (5.0 g, 21.8 mmol) was reacted with DABCO (2.9 g, 26.1 mmol), ClPPh2 (4.8 mL, 5.8 g, 26.1 mmol) and BH3·THF (43.6 mL, 43.6 mmol) in CH2Cl2 (40 mL). The crude product was purified by flash column chromatography (cyclohexane–EtOAc, 50:1) to afford 3c.

Yield: 8.95 g (20.95 mmol, 96%); white solid; mp 144 °C; Rf = 0.27 (cyclohexane–EtOAc, 50:1).

IR (neat): 3057, 2964, 2922, 2867, 2386, 2348, 2243, 1961, 1891, 1815, 1601, 1474, 1436, 1391, 1380, 1361, 1334, 1311, 1266, 1251, 1179, 1162, 1108, 1095, 1057, 1027, 998, 963, 906, 830, 768, 688 cm–1.

1H NMR (300 MHz, CDCl3): δ = 8.03–7.96 (m, 4 H, ArH), 7.52–7.43 (m, 6 H, ArH), 7.03 (q, J = 8.0 Hz, 2 H, ArH), 2.71 [dt, J = 13.6, 6.8 Hz, 1 H, CH(CH3)2], 2.32 (s, 3 H, CH3), 0.95 [d, J = 6.8 Hz, 6 H, (CH3)2].

13C NMR (APT, 75 MHz, CDCl3): δ = 148.6 (d, J = 5.6 Hz, C1), 140.2 (d, J = 2.1 Hz, CqAr), 136.9 (CqAr), 133.2 (d, J = 64.9 Hz, CqAr), 131.7 (d, J = 1.7 Hz, CHAr), 131.1 (d, J = 11.6 Hz, CHAr), 128.4 (d, J = 10.9 Hz, CHAr), 127.2 (CHAr), 124.6 (CHAr), 119.5 (d, J = 2.5 Hz, C2), 28.0 [CH(CH3)2], 23.4 (CH3), 22.9 [CH(CH3)2].

31P NMR {1H}(121 MHz, CDCl3): δ = 108.3 (d, J = 73.9 Hz, O-PR2).

11B NMR {1H} (96 MHz, CDCl3): δ = –124.8 (br s, BH3).

GC-MS: m/z = 229 (10), 227 (10), 201 (17), 183 (100), 171 (6), 152 (21), 133 (19), 115 (31), 108 (77), 91 (27), 77 (61), 65 (13), 51 (40), 43 (29).

HRMS (ESI): m/z [M + Na]+ calcd for C22H25BBrNaOP: 448.0847977; found: 448.08478.


#

(2-Bromo-6-ethylphenoxy)diphenylphosphine Borane Complex (3d)

Following the same protocol described for 3a, bromophenol 2d (14.7 g, 73.1 mmol) was reacted with DABCO (9.8 g, 87.7 mmol), ClPPh2 (15.7 mL, 19.3 g, 87.7 mmol) and BH3·THF (146.0 mL, 146.2 mmol) in CH2Cl2 (150 mL). The crude product was purified by flash column chromatography (cyclohexane–EtOAc, 50:1) to afford 3d.

Yield: 27.1 g (67.9 mmol, 93%); white solid; mp 145 °C; Rf = 0.55 (cyclohexane–EtOAc, 50:1).

IR (neat): 3056, 2966, 2930, 2872, 2384, 2274, 1588, 1481, 1455, 1434, 1331, 1255, 1208, 1169, 1109, 1091, 1056, 997, 896, 851, 837, 763, 732, 693 cm–1.

1H NMR (300 MHz, CDCl3): δ = 8.03–7.96 (m, 4 H, ArH), 7.52–7.45 (m, 6 H, ArH), 7.36 (dd, J = 7.9, 1.4 Hz, 1 H, ArH), 7.10 (dd, J = 7.6, 1.0 Hz, 1 H, ArH), 6.96 (td, J = 7.8, 1.0 Hz, 1 H, ArH), 2.29 (q, J = 7.5 Hz, 2 H, CH2), 0.94 (t, J = 7.5 Hz, 3 H, CH3).

13C NMR (APT, 75 MHz, CDCl3): δ = 149.4 (d, J = 5.5 Hz, C1), 138.9 (d, J = 2.8 Hz, CqAr), 133.1 (d, J = 64.7 Hz, CqAr), 131.9 (d, J = 2.5 Hz, CHAr), 131.1 (d, J = 11.7 Hz, CHAr), 131.0 (d, J = 1.5 Hz, CHAr), 128.5 (d, J = 10.9 Hz, CHAr), 128.4 (d, J = 1.5 Hz, CHAr), 126.2 (d, J = 1.8 Hz, CHAr), 117.0 (d, J = 3.2 Hz, C2), 24.9 (CH2), 14.0 (CH3).

31P NMR {1H}(121 MHz, CDCl3): δ = 109.2 (d, J = 76.8 Hz, O-PR2).

11B NMR {1H} (96 MHz, CDCl3): δ = –124.8 (br s, BH3).

GC-MS: m/z = 384 (13) [M – BH3]+, 317 (33), 305 (29), 214 (21), 202 (100), 186 (54), 139 (25), 125 (56), 108 (23).

HRMS (EI, 70 eV): m/z [M-BH3]+ calcd for C20H18BrOP: 384.0278; found: 384.027.


#

2-Boranatodiphenylphosphanyl-4,6-di-tert-pentylphenol (4a); Typical Procedure C

A 500 mL Schlenk flask was charged with borane-protected phosphinite 3a (35.2 g, 69 mmol, 1.0 equiv) and THF (200 mL) under argon. The solution was cooled to 0 °C before n-BuLi (64.7 mL, 104 mmol, 1.5 equiv) was added by using a syringe over 30 min. The resulting yellow to red solution was stirred for 2 h at 0 °C and then quenched with deionized H2O (200 mL). The mixture was transferred into a separatory funnel and the organic layer was collected. The aqueous layer was extracted with MTBE (3 × 100 mL) and the combined organic layers were washed with sat. aq NH4Cl (250 mL), dried over MgSO4 and filtered through a glass frit. Removal of solvent under reduced pressure afforded the crude product as a colorless oil, which was crystallized from hot EtOAc at 0 °C over 2 d to yield the desired product 4a (21.53 g, 72%) as white crystals. The mother liquor was purified by flash column chromatography on silica gel (cyclohexane). The solvent was removed in vacuo to yield additional 4a (7.78 g, 26%).

White solid; mp 128 °C; Rf = 0.35 (cyclohexane).

IR (neat): 3361, 3046, 2959, 2866, 2375, 1953, 1883, 1810, 1586, 1570, 1453, 1435, 1380, 1361, 1340, 1296, 1236, 1187, 1133, 1104, 1066, 1026, 998, 906, 846, 763, 739, 690 cm–1.

1H NMR (300 MHz, CDCl3): δ = 7.55–7.41 (m, 11 H, OH, ArH), 7.33 (d, J = 2.2 Hz, 1 H, H-5), 6.57 (dd, J = 11.6, 2.3 Hz, 1 H, H-3), 1.85 (q, J = 7.4 Hz, 2 H, CH 2CH3), 1.45–1.36 [m, 8 H, CH 2CH3, C(CH3)2], 1.05 [s, 6 H, C(CH3)2], 0.64–0.53 (m, 6 H, 2 × CH2CH 3).

13C NMR (APT, 75 MHz, CDCl3): δ = 157.0 (d, J = 9.8 Hz, C1), 140.2 (d, J = 7.9 Hz, C4), 136.2 (d, J = 5.8 Hz, C6), 132.9 (d, J = 9.8 Hz, CHAr), 131.4 (d, J = 1.5 Hz, CHAr), 130.5 (C5), 129.4 (d, J = 3.3 Hz, C3), 128.8 (d, J = 10.5 Hz, CHAr), 128.6 (d, J = 61.5 Hz, C2), 110.9 (d, J = 59.5 Hz, CqAr), 38.9 (Cq), 37.4 (Cq), 36.8 (CH2CH3), 32.9 (CH2CH3), 28.2 [C(CH3)2], 27.8 [C(CH3)2], 9.5 (CH2 CH3), 9.0 (CH2 CH3).

31P NMR {1H} (121 MHz, CDCl3): δ = 13.6 (d, J = 51.4 Hz, PR3).

11B NMR {1H} (96 MHz, CDCl3): δ = –119.6 (br s, BH3).

GC-MS: m/z = 418 (83) [M – BH3]+, 403 (55), 389 (100), 375 (61), 362 (25), 347 (16), 333 (19), 311 (22), 205 (13), 183 (33), 108 (20), 87 (18), 43 (13).

HRMS (EI, 70 eV): m/z [M – BH3]+ calcd for C28H35OP: 418.2425; found: 418.242.


#

2-Boranatodiphenylphosphanyl-6-tert-pentylphenol (4b)

Following the same protocol described for 4a, phosphinite 3b (35.3 g, 0.08 mol) was reacted with n-BuLi (75.0 mL, 0.12 mol) in THF (200 mL). The crude product was crystallized from EtOAc and the mother liquor was purified by flash column chromatography (cyclohexane) to give the desired product 4b.

Yield: 27.9 g (0.077 mol, 96%); white solid; mp 164 °C; Rf = 0.30 (cyclohexane).

IR (neat): 3352, 3056, 2958, 2872, 2375, 1576, 1480, 1467, 1435, 1419, 1383, 1360, 1341, 1225, 1199, 1158, 1120, 1104, 1068, 1027, 998, 909, 827, 741, 699, 690 cm–1.

1H NMR (300 MHz, CDCl3): δ = 7.64 (d, J = 2.0 Hz, 1 H, ArH), 7.56–7.38 (m, 11 H, ArH, OH), 6.82 (td, J = 7.7, 1.6 Hz, 1 H, ArH), 6.71–6.64 (m, 1 H, ArH), 1.86 (q, J = 7.5 Hz, 2 H, CH 2CH3), 1.36 [s, 6 H, C(CH3)2], 0.62 (t, J = 7.5 Hz, 3 H, CH2CH 3).

13C NMR (APT, 75 MHz, CDCl3): δ = 159.3 (d, J = 9.5 Hz, C1), 137.2 (d, J = 5.4 Hz, C6), 133.0 (d, J = 9.9 Hz, CHAr), 132.6 (d, J = 1.9 Hz, CHAr), 132.0 (d, J = 3.4 Hz, CHAr), 131.5 (d, J = 2.5 Hz, CHAr), 128.9 (d, J = 10.6 Hz, CHAr), 128.2 (d, J = 61.8 Hz, C2), 120.0 (d, J = 8.7 Hz, CHAr), 112.3 (d, J = 59.2 Hz, Cq), 38.9 (d, J = 1.4 Hz, Cq), 32.8 (CH2), 27.8 [C(CH3)2], 9.6 (CH2 CH3).

31P NMR {1H} (121 MHz, CDCl3): δ = 12.9 (d, J = 73.8 Hz, PR3).

11B NMR {1H} (96 MHz, CDCl3): δ = –119.7 (br s, BH3).

GC-MS: m/z = 348 (80) [M – BH3]+, 333 (77), 319 (85), 305 (100), 300 (85), 221 (15), 199 (15), 183 (80), 152 (18), 107 (31), 78 (30), 51 (15).

HRMS (EI, 70 eV): m/z [M – BH3]+ calcd for C23H25OP: 348.1643; found: 348.164.


#

2-Boranatodiphenylphosphanyl-3-methyl-6-isopropylphenol (4c)

Following the same protocol described for 4a, phosphinite 3c (5.0 g, 11.71 mmol) was reacted with n-BuLi (11.0 mL, 17.57 mmol) in THF (34 mL). The crude product was crystallized from EtOAc and the mother liquor was purified by flash column chromatography (cyclohexane–EtOAc, 50:1) to give the desired product 4c.

Yield: 3.87 g (11.11 mmol, 95%); white solid; mp 110 °C; Rf = 0.32 (cyclohexane–EtOAc, 50:1).

IR (neat): 3337, 3056, 2958, 2927, 2867, 2388, 2303, 2113, 1961, 1896, 1816, 1590, 1574, 1471, 1435, 1392, 1378, 1361, 1344, 1317, 1280, 1256, 1208, 1181, 1162, 1126, 1101, 1061, 1026, 998, 958, 907, 809, 767, 735, 695 cm–1.

1H NMR (300 MHz, CDCl3): δ = 8.61 (d, J = 1.6 Hz, 1 H, OH), 7.62–7.56 (m, 4 H, ArH), 7.51–7.40 (m, 6 H, ArH), 7.31 (d, J = 7.7 Hz, 1 H, ArH), 6.71 (dd, J = 7.7, 1.8 Hz, 1 H), 3.38 [dt, J = 13.7, 6.9 Hz, 1 H, CH(CH3)2], 1.68 (s, 3 H, CH3), 1.24 [d, J = 6.9 Hz, 6 H, (CH3)2].

13C NMR (APT, 75 MHz, CDCl3): δ = 160.4 (d, J = 11.9 Hz, C1), 140.9 (CqAr), 135.5 (d, J = 5.7 Hz, CqAr), 132.0 (d, J = 9.8 Hz, CHAr), 130.9 (d, J = 1.9 Hz, CHAr), 130.7 (CHAr), 129.0 (d, J = 62.1 Hz, C2), 128.9 (d, J = 10.7 Hz, CHAr), 123.6 (d, J = 6.9 Hz, CHAr), 107.0 (d, J = 56.6 Hz, Cq), 26.8 [CH(CH3)2], 23.9 (d, J = 3.6 Hz, CH3), 22.5 [CH(CH3)2].

31P NMR {1H} (121 MHz, CDCl3): δ = 10.6 (d, J = 49.8 Hz, PR3).

11B NMR {1H} (96 MHz, CDCl3): δ = –115.7 (br s, BH3).

GC-MS: m/z = 335 (10) [M – BH3]+, 183 (10), 153 (3), 132 (5), 115 (8), 108 (8), 91 (10), 78 (100), 65 (7), 51 (15), 41 (21).

HRMS (ESI): m/z [M + Na]+ calcd for C22H26BNaOP: 370.1742852; found: 370.17438.


#

2-Boranatodiphenylphosphanyl-6-ethylphenol (4d)

Following the same protocol described for 4a, phosphinite 3d (27.0 g, 67.7 mmol) was reacted with n-BuLi (63.5 mL, 101.6 mmol) in THF (200 mL). The crude product was crystallized from EtOAc and the mother liquor was purified by flash column chromatography (cyclohexane–EtOAc, 50:1) to give the desired product 4d.

Yield: 20.6 g (64.3 mmol, 95%); white solid; mp 101 °C; Rf = 0.50 (cyclohexane–EtOAc, 20:1).

IR (neat): 3359, 3053, 2963, 2920, 2860, 2375, 1583, 1481, 1435, 1340, 1221, 1178, 1149, 1103, 1063, 1027, 998, 830, 739, 690 cm–1.

1H NMR (300 MHz, CDCl3): δ = 7.63 (s, 1 H, OH), 7.56–7.42 (m, 10 H, ArH), 7.31 (d, J = 7.3 Hz, 1 H, ArH), 6.83 (t, J = 8.1 Hz, 1 H, ArH), 6.73 (m, 1 H, ArH), 2.68 (q, J = 7.5 Hz, 2 H, CH2), 1.22 (t, J = 7.5 Hz, 3 H, CH3).

13C NMR (APT, 75 MHz, CDCl3): δ = 158.4 (d, J = 9.5 Hz, Cq), 133.4 (d, J = 5.8 Hz, Cq), 133.3 (d, J = 2.1 Hz, CHAr), 133.0 (d, J = 9.9 Hz, CHAr), 131.9 (d, J = 3.1 Hz, CHAr), 131.5 (d, J = 2.5 Hz, CHAr), 128.9 (d, J = 10.6 Hz, CHAr), 128.2 (d, J = 61.9 Hz, Cq), 120.3 (d, J = 8.4 Hz, CHAr), 111.0 (d, J = 58.6 Hz, Cq), 23.2 (d, J = 1.7 Hz, CH2), 13.7 (CH3).

31P NMR {1H} (121 MHz, CDCl3): δ = 12.5 (d, J = 68.2 Hz, PR3).

11B NMR {1H} (96 MHz, CDCl3): δ = –119.5 (br s, BH3).

GC-MS: m/z = 306 (100) [M – BH3]+, 291 (12), 227 (23), 199 (30), 183 (46), 152 (15), 107 (21), 78 (38).

HRMS (EI, 70 eV): m/z [M – BH3]+ calcd for C20H19OP: 306.1173; found: 306.117.


#

(3aR,8aR)-6-[2-(Diphenylphosphino)-4,6-di-tert-pentylphenoxy]-2,2-dimethyl-4,4,8,8-tetraphenyltetrahydro[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepine (L*-A4); Typical Procedure D

A flame-dried 250 mL Schlenk flask was charged under argon with borane-protected phosphine 4a (5.0 g, 11.56 mmol, 1.0 equiv), DABCO (10.37 g, 92.48 mmol, 8.0 equiv) and CH2Cl2 (70 mL). The resulting solution was stirred for 10 min at r.t., then cooled to 0 °C before PCl3 (2 M in CH2Cl2, 6.94 mL, 13.88 mmol, 1.2 equiv) was added dropwise by using a syringe over 30 min. The resulting slurry was stirred for 30 min at this temperature, then allowed to warm to r.t. and stirred for 3 h. The reaction mixture was cooled to 0 °C and a solution of (R,R)-TADDOL (8.09 g, 17.34 mmol, 1.5 equiv) in CH2Cl2 (70 mL) was added dropwise by using a syringe over 30 min. The resulting suspension was stirred for 30 min at 0 °C, then allowed to come to r.t. and stirred for 20 h. The reaction mixture was filtered over silica gel and, after concentration of the filtrate by rotary evaporation, the crude product was purified by flash column chromatography on silica gel (cyclohexane–CH2Cl2, 4:1). The fractions containing pure product were concentrated by rotary evaporation and dried in vacuo to yield ligand L*-A4 (5.27 g, 50%) as a white foam. Impure fractions were collected separately, concentrated in vacuo and subjected to a second chromatographic purification to give additional L*-A4 (1.47 g, 14%).

Mp 115–120 °C; Rf = 0.25 (cyclohexane–CH2Cl2, 4:1). [α]λ 20 (c = 0.5, CHCl3): [α]589 –154.4, [α]546 –185.8, [α]405 –416.0, [α]365 –580.1.

IR (neat): 3053, 2959, 2866, 1950, 1886, 1806, 1763, 1583, 1490, 1473, 1443, 1430, 1420, 1380, 1326, 1293, 1260, 1236, 1208, 1163, 1103, 1086, 1043, 1030, 1010, 976, 930, 882, 846, 830, 783, 693 cm–1.

1H NMR (300 MHz, CDCl3): δ = 7.58–7.40 (m, 8 H, ArH), 7.25–7.03 (m, 23 H, ArH), 6.83 (br s, 1 H, ArH), 5.35 (d, J = 8.2 Hz, 1 H, CH), 5.14 (d, J = 8.2 Hz, 1 H, CH), 1.91 (q, J = 7.0 Hz, 2 H, CH 2CH3), 1.42–1.35 (m, 5 H, CH 2CH3, CH3), 1.29 (s, 3 H, CH3), 1.05 (s, 3 H, CH3), 1.03 (s, 3 H, CH3), 0.85 (s, 3 H, CH3), 0.52–0.46 (m, 6 H, 2 × CH2CH 3), 0.44 (s, 3 H, CH3).

13C NMR (APT, 75 MHz, CDCl3): δ = 153.8, 153.5, 145.5, 145.2, 142.7, 141.7, 141.2, 139.2, 138.8, 138.2, 133.3, 133.1, 132.9, 132.6, 129.1, 128.9, 128.0, 127.9, 127.8, 127.7, 127.5, 127.3, 127.1, 126.9, 126.8, 125.9, 125.8, 113.2, 86.5, 86.3, 82.9, 81.8, 81.6, 81.0, 39.1, 37.6, 36.8, 33.8, 28.9, 28.6, 28.3, 26.9, 26.1, 9.5, 8.9.

31P NMR {1H} (121 MHz, CDCl3): δ = 139.8 [d, J = 148.4 Hz, P(OR)3], –18.7 (d, J = 148.4 Hz, PR3).

HRMS (ESI, MeOH/CH2Cl2, Ag+CF3COO–): m/z calcd for C59H62AgO5P2: 1019.3123; found: 1019.3230.


#

(3aR,8aR)-6-[2-(Diphenylphosphino)-6-tert-pentylphenoxy]-2,2-dimethyl-4,4,8,8-tetraphenyltetrahydro[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepine (L*-A5)

Following the same protocol described for L*-A4, phosphine 4b (1.81 g, 5.0 mmol) was reacted with DABCO (4.49 g, 40.0 mmol) and PCl3 (3.0 mL, 6.0 mmol) in CH2Cl2 (30 mL) before (R,R)-TADDOL (3.50 g, 7.5 mmol) in CH2Cl2 (30 mL) was added. The crude product was purified by flash column chromatography (cyclohexane–CH2Cl2, 5:1) to afford L*-A5.

Yield: 2.19 g (2.6 mmol, 52%); white foam; mp 120–121 °C; Rf = 0.60 (cyclohexane–CH2Cl2, 2:1); [α]λ 20 (c = 0.5, CHCl3): [α]589 –176.9, [α]546 –212.4, [α]405 –480.1, [α]365 –673.5.

IR (neat): 3054, 2959, 2871, 1951, 1811, 1583, 1492, 1477, 1445, 1432, 1401, 1380, 1270, 1245, 1206, 1165, 1086, 1048, 1032, 1011, 883, 796, 737, 694, 664, 641 cm–1.

1H NMR (300 MHz, CDCl3): δ = 7.57–7.40 (m, 8 H, ArH), 7.32–7.06 (m, 23 H, ArH), 6.93–6.86 (m, 2 H, ArH), 5.37 (d, J = 8.2 Hz, 1 H, CH), 5.17 (d, J = 8.2 Hz, 1 H, CH), 1.94 (q, J = 7.2 Hz, 2 H, CH2), 1.41 (s, 3 H, CH3), 1.26 (s, 3 H, CH3), 0.85 (s, 3 H, CH3), 0.49 (t, J = 7.4 Hz, 3 H, CH2CH 3), 0.44 (s, 3 H, CH3).

13C NMR (APT, 75 MHz, CDCl3): δ = 156.2, 155.8, 145.5, 145.2, 141.7, 141.6, 141.1, 139.5, 138.6, 138.4, 138.3, 137.8, 137.7, 134.8, 133.3, 133.2, 133.1, 133.0, 130.2, 129.0, 128.9, 128.2, 128.1, 128.0, 127.9, 127.8, 127.5, 127.4, 127.3, 127.2, 127.0, 126.9, 126.8, 122.9, 113.3, 86.7, 86.5, 83.1, 83.0, 81.8, 81.6, 81.1, 81.0, 38.9, 33.6, 28.9, 28.6, 26.9, 26.1, 9.6.

31P NMR {1H} (121 MHz, CDCl3): δ = 139.2 [d, J = 151.6 Hz, P(OR)3], –19.8 (d, J = 151.6 Hz, PR3).

HRMS (ESI, MeOH/CH2Cl2): m/z [M + Na]+ calcd for C54H52NaO5P2: 865.3132; found: 865.3200.


#

(3aR,8aR)-6-[2-(Diphenylphosphino)-6-isopropyl-3-methylphenoxy]-2,2-dimethyl-4,4,8,8-tetraphenyltetrahydro[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepine (L*-A6)

Following the same protocol described for L*-A4, phosphine 4c (1.05 g, 3.0 mmol) was reacted with DABCO (2.69 g, 24.0 mmol) and PCl3 (1.8 mL, 3.6 mmol) in CH2Cl2 (30 mL) before (R,R)-TADDOL (2.10 g, 4.5 mmol) in CH2Cl2 (25 mL) was added. The crude product was purified by flash column chromatography (cyclohexane–CH2Cl2, 5:1) to afford L*-A6.

Yield: 1.74 g (2.1 mmol, 70%); white foam; mp 123–125 °C; Rf = 0.40 (cyclohexane–CH2Cl2, 2:1); [α]λ 20 (c = 1.0, CHCl3): [α]589 –200.6, [α]546 –242.3, [α]405 –549.0.

IR (neat): 3054, 2970, 2933, 2823, 1951, 1885, 1807, 1583, 1493, 1478, 1467, 1445, 1433, 1383, 1361, 1329, 1234, 1201, 1165, 1082, 1048, 1034, 1026, 1007, 971, 955, 930, 916, 885, 850, 824, 783, 738, 723, 695, 664 cm–1.

1H NMR (300 MHz, CDCl3): δ = 7.55–7.43 (m, 8 H, ArH), 7.27–7.01 (m, 23 H, ArH), 6.89 (d, J = 7.8 Hz, 1 H, ArH), 5.32 (d, J = 8.2 Hz, 1 H, CH), 5.06 (d, J = 8.2 Hz, 1 H, CH), 3.87 [dt, J = 13.6, 6.8 Hz, 1 H, CH(CH3)2], 1.64 (s, 3 H, CH3), 1.20 (d, J = 6.9 Hz, 3 H, CH3), 1.07 (d, J = 6.8 Hz, 3 H, CH3), 0.92 (s, 3 H, CH3), 0.43 (s, 3 H, CH3).

13C NMR (APT, 75 MHz, CDCl3): δ = 155.2, 154.8, 145.6, 145.4, 143.4, 141.4, 141.2, 139.0, 136.6, 136.4, 136.1, 136.0, 135.8, 131.9, 131.6, 131.2, 131.0, 128.9, 128.6, 128.1, 128.0, 127.9, 127.8, 127.6, 127.5, 127.4, 127.3, 127.2, 127.1, 127.0, 125.4, 125.2, 113.0, 86.0, 85.9, 82.8, 82.1, 81.9, 81.0, 27.1, 26.7, 26.0, 23.9, 22.9, 22.8.

31P NMR {1H} (121 MHz, CDCl3): δ = 145.4 [d, J = 99.4 Hz, P(OR)3], –19.6 (d, J = 99.4 Hz, PR3).

HRMS (ESI): m/z [M + H]+ calcd for C53H51O5P2: 829.3206241; found: 829.32128.


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(3aR,8aR)-6-[2-(Diphenylphosphino)-6-ethylphenoxy]-2,2-dimethyl-4,4,8,8-tetraphenyltetrahydro[1,3]dioxolo[4,5-e][1,3,2]dioxaphosphepine (L*-A7)

Following the same protocol described for L*-A4, phosphine 4d (0.96 g, 3.0 mmol) was reacted with DABCO (2.69 g, 24.0 mmol) and PCl3 (1.8 mL, 3.6 mmol) in CH2Cl2 (30 mL) before (R,R)-TADDOL (2.10 g, 4.5 mmol) in CH2Cl2 (25 mL) was added. The crude product was purified by flash column chromatography (cyclohexane–CH2Cl2, 10:1) to afford L*-A7.

Yield: 1.32 g (1.65 mmol, 55%); white foam; mp 113–115 °C; Rf = 0.20 (cyclohexane–CH2Cl2, 2:1); [α]λ 20 (c = 0.5, CHCl3): [α]589 –156.2, [α]546 –188.7, [α]405 –435.3, [α]365 –619.9.

IR (neat): 3054, 2984, 2963, 2931, 2871, 1597, 1583, 1492, 1445, 1432, 1419, 1380, 1370, 1328, 1241, 1203, 1164, 1086, 1048, 1033, 1016, 905, 882, 815, 800, 769, 731, 694, 665 cm–1.

1H NMR (300 MHz, CDCl3): δ = 7.77 (d, J = 7.8 Hz, 2 H, ArH), 7.61 (d, J = 8.0 Hz, 2 H, ArH), 7.51 (t, J = 7.1 Hz, 4 H, ArH), 7.33–7.28 (m, 15 H, ArH), 7.24–7.18 (m, 8 H, ArH), 7.02 (t, J = 7.6 Hz, 1 H, ArH), 6.73 (d, J = 7.6 Hz, 1 H, ArH), 5.19 (s, 2 H, 2 × CH), 2.96 (m, 1 H, CH2A), 2.77 (m, 1 H, CH2B), 1.19 (t, J = 7.5 Hz, 3 H, CH2CH 3), 1.13 (s, 3 H, CH3), 0.45 (s, 3 H, CH3).

13C NMR (APT, 75 MHz, CDCl3): δ = 153.5, 153.4, 145.7, 145.4, 141.5, 141.0, 137.4, 137.3, 137.2, 137.1, 136.7, 133.9, 133.8, 133.7, 133.6, 132.4, 130.2, 129.9, 129.8, 129.2, 129.0, 128.3, 128.2, 128.1, 128.0, 127.6, 127.5, 127.4, 127.3, 127.2, 127.0, 124.5, 112.7, 85.4, 85.3, 82.9, 82.8, 82.0, 81.9, 81.3, 81.2, 27.3, 25.8, 23.8, 14.1.

31P NMR {1H} (121 MHz, CDCl3): δ = 146.2 [d, J = 62.1 Hz, P(OR)3], –18.3 (d, J = 62.8 Hz, PR3).

HRMS (ESI): m/z [M + H]+ calcd for C51H47O5P2: 801.2893240; found: 801.28982.


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(11bS)-4-[2-(Diphenylphosphino)-4,6-di-tert-pentylphenoxy]dinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine (L*-B1)

Following the same protocol described for L*-A4, phosphine 4a (1.0 g, 2.32 mmol) was reacted with DABCO (2.08 g, 18.56 mmol) and PCl3 (1.4 mL, 2.8 mmol) in CH2Cl2 (14 mL) before (S)-BINOL (1.0 g, 3.48 mmol) in CH2Cl2 (20 mL) was added. The crude product was purified by flash column chromatography (cyclohexane–CH2Cl2, 4:1) to afford L*-B1.

Yield: 0.65 g (0.88 mmol, 38%); white foam; mp 120–121 °C; Rf = 0.30 (cyclohexane–CH2Cl2, 4:1); [α]λ 20 (c = 0.5, CHCl3): [α]589 +84.9, [α]546 +95.2, [α]405 +12.9, [α]365 –576.5.

IR (neat): 3051, 2958, 2871, 1618, 1587, 1508, 1461, 1432, 1420, 1360, 1326, 1262, 1230, 1199, 1186, 1102, 1069, 952, 897, 850, 820, 781, 742, 694 cm–1.

1H NMR (300 MHz, CDCl3): δ = 7.94–7.80 (m, 3 H, ArH), 7.68 (d, J = 8.8 Hz, 1 H, ArH), 7.48 (d, J = 8.8 Hz, 1 H, ArH), 7.43–7.13 (m, 17 H, ArH), 6.80–6.77 (m, 2 H, ArH), 1.70–1.53 (m, 2 H, CH2), 1.43–1.41 (m, 2 H, CH2), 1.26 (s, 3 H, CH3), 1.18 (s, 3 H, CH3), 1.07 (s, 3 H, CH3), 1.06 (s, 3 H, CH3), 0.55 (t, J = 7.4 Hz, 3 H, CH2CH 3), 0.47 (t, J = 7.4 Hz, 3 H, CH2CH 3).

13C NMR (APT, 75 MHz, CDCl3): δ = 148.9, 148.8, 147.7, 147.6, 144.0, 138.9, 134.1, 133.9, 133.4, 133.2, 132.9, 132.3, 131.5, 131.4, 130.9, 130.0, 129.2, 128.6, 128.5, 128.4, 128.3, 128.1, 127.1, 126.9, 126.0, 125.7, 124.8, 124.5, 122.2, 121.9, 38.9, 37.7, 36.8, 33.4, 28.9, 28.6, 28.2, 9.4, 9.0.

31P NMR {1H} (121 MHz, CDCl3): δ = 143.2 [d, J = 146.3 Hz, P(OR)3], –14.7 (d, J = 146.4 Hz, PR3).


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Acknowledgment

This work was supported by the Fonds der Chemischen Industrie (doctorate stipend to A.F.), the University of Cologne, and by ­SusChemSys, a programme of the State of North Rhine-Westphalia, Germany, co-financed by the European Union through ERDF funds. We also acknowledge Rockwood Lithium, Frankfurt, for generous gifts of butyllithium.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis.
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Figure 1 General architecture of modular phosphine–phosphite ligands (L*) derived from chiral diols
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Scheme 1 General scheme for the synthesis of chiral phosphine–phosphite ligands of type L*
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Scheme 2 Performance of ligands of type L*-A in selected C–C bond-forming reactions
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Figure 2 New ligands described herein
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Scheme 3 Conversion of dibrominated by-products 3′ into the desired intermediates 4 in a ‘self-purification’ process
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Scheme 4 Multigram synthesis of ligands L*-A4–7 and L*-B1
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Scheme 5 Cu-catalyzed enantioselective 1,4-addition of Et-MgBr to cyclohexenone in the presence of ligand L*-A4