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StePHOX, a New Family of Optically Active,

Highly Tunable Phosphine-Oxazoline Ligands:

Syntheses and Applications

Stéphane Trudeau and James P. Morken*

Department of Chemistry, Venable and Kenan Laboratories

University of North Carolina, Chapel Hill, NC 27599-3290

Supplementary Material

Table of contents

1) General Remarks ............................ S 2

2) Experimental details ....................... S 3

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1) General Remarks:

All reactions were performed under nitrogen atmosphere with flame dried glassware. Tetrahydrofuran (THF) was distilled from sodium/benzophenone under nitrogen atmosphere immediately prior to use. Dichloromethane, Et2O, and toluene were dried by being passed through a column of neutral alumina under argon atmosphere immediately prior to use. All other solvents were used as received.

1H NMR (400 MHz) chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as the internal standard (CDCl3: 7.24 ppm). Data are reported as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qu = quintuplet, br = broad, m = multiplet), coupling constants (Hz) and assignment. 13C NMR (100 MHz) chemical shifts are reported in ppm from tetramethylsilane with the solvent as the internal standard (CDCl3: 77.0 ppm). 31P NMR (161 MHz) chemical shifts are reported in ppm.

Liquid chromatography was performed using forced flow (flash chromatography) on silica gel (SiO2, 32 to 63 µm). Thin layer chromatography (TLC) was performed on 0.25 mm silica gel plates. Analytical high performance liquid chromatography (HPLC) was performed using a Daicel Chiralcel OD-H column.

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2) Experimental details

1) NaOEtEtOH, 78oC CO2Et

OTf

2) Tf2O, 2,6-lutidineCH2Cl2

10

O O

Triflate 10. Finely cut pieces of sodium (3.93 g, 0.17 mol) were added to a cooled (0oC) solution of absolute EtOH (90 mL). The solution was stirred while warming up to room temperature until all sodium was dissolved. Coumarin (5.0 g, 34.2 mmol) dissolved in absolute EtOH (47 mL) was then added to the first solution. The resulting yellow mixture was then stirred at reflux for 16 h. Once cooled to room temperature, the mixture was concentrated under reduced pressure. A saturated aqueous solution of NH4Cl (200 mL) was added to the crude reaction mixture and it was extracted with EtOAc (3 x 100 mL). The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was dissolved in 1:1 hexane/EtOAc (100 mL) and filtered through a pad of silica gel. The pad was rinsed with 1:1 hexane/EtOAc (2 x 100 mL) and the filtrate was then concentrated under reduced pressure to give the desired product (5.57 g) as a white-beige solid. This solid (4.15 g, 21.6 mmol) was dissolved in CH2Cl2 (70 mL) and 2,6-lutidine (3.8 mL, 32.4 mmol) was added. The solution was cooled to –78oC and a solution of trifluoromethanesulfonic anhydride (4.5 mL, 27.0 mmol) in CH2Cl2 (38 mL) was added via canula. The reaction mixture was stirred 0.5 h at –78oC, 0.5 h at 0oC and 2 h at room temperature. Saturated aqueous NH4Cl (100 mL) was then added and the mixture was extracted with CH2Cl2 (3 x 100 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (1/0 to 9/1 : hexane/EtOAc) to give triflate 10 (8.28 g, 75% over 2 steps) as a yellow oil. IR (thin film, ν cm-1): 2987, 1717, 1642, 1424, 1214, 1140. 1H NMR: δ 7.85 (1H, d, J = 16.0 Hz), 7.68 (1H, dd, J = 7.8, 1.7 Hz), 7.47-7.33 (3H, m), 6.48 (1H, d, J = 16.0 Hz), 4.26 (2H, q, J = 7.1 Hz), 1.32 (3H, t, J = 7.1 Hz). 13C NMR: δ 165.8, 147.6, 135.7, 131.5, 128.6, 128.2, 128.0, 122.6, 122.2, 117.0, 60.8, 14.1. MS (ESI) (M+H)+: 325.1. HRMS (ESI) (M+Na)+ calc’d for C12H11F3O5SNa: 347.0171. Found: 347.0178.

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AD-mix-βMsNH2CO2Et

OTfOH

OTf

t-BuOH, H2O

10 11

OH

CO2Et

Diol 11. To a stirred solution of triflate 10 (8.11 g, 25.0 mmol) in tBuOH (125 mL) and H2O (125 mL) was added methanesulfonamide (2.38 g, 25.0 mmol) and AD-mix-β (35 g). The mixture was stirred at room temperature for 48 h then sodium sulfite (7.57 g, 60.0 mmol) was added. The resulting mixture was stirred 0.5 h and then H2O (200 mL) was added. The mixture was extracted with CH2Cl2 (3 x 150 mL). The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was recrystallized in hexane (100 mL) to give a 1st crop of white needles (2.51 g). The mother liquor was purified by flash chromatography (9/1 to 0/1 : hexane/EtOAc) to give the desired product (5.8 g) which was recrystallized in hexane to give a 2nd crop of white needles (2.42 g). Mother liquor was recrystallized a 3rd time to give another crop of pure diol 11 (2.13 g) (total = 7.06 g, 79%). [α]25

D –10.5 (c 1.25 CHCl3). IR (thin film, ν cm-1): 3398, 2989, 1740, 1424, 1214, 1140. 1H NMR: δ 7.71-7.69 (1H, m), 7.44-7.37 (2H, m), 7.31-7.28 (1H, m), 5.37 (1H, dd, J = 7.5, 2.4 Hz), 4.34 (1H, dd, J = 5.6, 2.5 Hz), 4.29 (2H, q, J = 7.2 Hz), 3.29 (1H, d, J = 5.6 Hz), 2.92 (1H, d, J = 7.5 Hz), 1.29 (3H, t, J = 7.2 Hz). 13C NMR: δ 172.2, 146.1, 133.0, 129.8, 129.3, 128.5, 121.1, 119.0, 73.1, 68.5, 62.6, 13.9. MS (ESI) (M+H)+: 359.1; (M+Na)+: 381.2. HRMS (ESI) (M+Na)+ calc’d for C12H13F3O7SNa: 381.0226. Found: 381.0232. Chiral HPLC (Chiralcel OD-H, Daicel, 5% i-PrOH in hexane, 1.0 mL/min, wavelength: 220 nm) analysis of the product:

Diol 11

Racemic diol 11

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AD-mix-αMsNH2CO2Et

OTfOH

OTf

t-BuOH, H2O

10 ent-11

OH

CO2Et

Diol ent-11. [α]25D +10.8 (c 1.25 CHCl3). Chiral HPLC (Chiralcel OD-H, Daicel, 5% i-

PrOH in hexane, 1.0 mL/min, wavelength: 220 nm) analysis of the product:

Diol ent-11

Racemic diol 11

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CO2Et

OOOTfOTf OH (MeO)2CMe2

p-TsOH

acetone

11 12

OH

CO2Et

Acetonide 12. To a stirred solution of diol 11 (0.99 g, 2.76 mmol) in acetone (5.3 mL) was added 2,2-dimethoxypropane (2.1 mL) and p-toluenesulfonic acid (26 mg, 0.14 mmol). The solution was stirred at room temperature 16 h then Et3N was added to neutralize the acid and the solvent was then stripped off. The crude product was extracted with Et2O (3 x 10 mL) and saturated aqueous NaHCO3. The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (9/1 : hexane/EtOAc) to give acetonide 12 (1.00 g, 91%) as a colorless oil. [α]25

D –4.7 (c 1.35 CHCl3). IR (thin film, ν cm-1): 2993, 2943, 1760, 1424, 1216, 1142. 1H NMR: δ 7.68-7.65 (1H, m), 7.46-7.39 (2H, m), 7.32-7.30 (1H, m), 5.44 (1H, d, J = 7.6 Hz), 4.30 (1H, d, J = 7.6 Hz), 4.20 (2H, tt, J = 14.3, 7.2 Hz), 1.60 (3H, s), 1.55 (3H, s), 1.22 (3H, t, J = 7.2 Hz). 13C NMR: δ 169.3, 147.5, 130.3, 128.9, 128.8, 121.2, 120.1, 117.0, 112.2, 81.0, 74.5, 61.8, 26.8, 25.6, 13.8. MS (ESI) (M+H)+: 399.1. HRMS (ESI) (M+Na)+ calc’d for C15H17F3O7SNa: 421.0539. Found: 421.0548.

CO2Et

OOOTfOTf OH (MeO)2CMe2

p-TsOH

acetone

ent-11 ent-12

OH

CO2Et

Acetonide ent-12. [α]25D +5.2 (c 0.93 CHCl3).

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CO2Et

OOOTf

CO2Et

OOPh2P

O

DMSO, 120oC

Ph2P(O)H, i-Pr2NEtPd(OAc)2, dppp

12 13

Phosphine oxide 13. To a stirred solution of acetonide 12 (1.32 g, 3.31 mmol) in DMSO (66 mL) was added diphenylphosphine oxide (1.43 g, 7.06 mmol), palladium (II) acetate (164 mg, 0.73 mmol), 1,3-bis(diphenylphosphino)propane (0.30 g, 0.73 mmol) and N,N-diisopropylethylamine (1.15 mL, 6.63 mmol). The orange solution was stirred at 120oC for 3 h. The resulting dark red mixture was then cooled to room temperature and 5% aqueous HCl (400 mL) was added. The mixture was extracted with CH2Cl2 (3 x 100 mL). The combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (1/1 : hexane/EtOAc) to give phosphine oxide 13 (1.48 g, 99%) as a yellow foam. [α]25

D +33.7 (c 0.76 CHCl3). IR (thin film, ν cm-1): 2989, 1756, 1437, 1194, 1104. 1H NMR: δ 7.81 (1H, dd, J = 7.6, 3.9 Hz), 7.68-7.57 (5H, m), 7.54-7.39 (6H, m), 7.28-7.24 (1H, m), 7.05 (1H, dd, J = 13.9, 7.7 Hz), 6.06 (1H, d, J = 7.3 Hz), 4.43 (1H, d, J = 7.7 Hz), 4.26-4.12 (2H, m), 1.51 (3H, s), 1.26 (3H, s), 1.19 (3H, t, J = 7.1 Hz). 13C NMR: δ 169.0, 142.2 (d, JPC = 6.7 Hz), 133.3 (d, JPC = 102.9 Hz), 132.8 (d, JPC = 12.4 Hz), 132.4 (d, JPC = 104.5 Hz), 132.1 (d, JPC = 2.5 Hz), 131.9 (d, JPC = 9.6 Hz), 131.8 (d, JPC = 102.2 Hz), 131.5 (d, JPC = 2.7 Hz), 131.4 (d, JPC = 9.8 Hz), 131.3 (d, JPC = 4.7 Hz), 128.8 (d, JPC = 9.5 Hz), 128.1 (d, JPC = 12.2 Hz), 127.5 (d, JPC = 12.4 Hz), 111.0, 81.7, 76.6 (d, JPC = 5.4 Hz), 60.9, 26.7, 25.1, 13.6. 31P NMR: δ 32.9. MS (ESI) (M+H)+: 451.0. HRMS (ESI) (M+H)+ calc’d for C26H28O5P: 451.1669. Found: 451.1672; (M+Na)+ calc’d for C26H27O5PNa: 473.1488. Found: 473.1491.

CO2Et

OOOTf

CO2Et

OOPh2P

O

DMSO, 120oC

Ph2P(O)H, i-Pr2NEtPd(OAc)2, dppp

ent-12 ent-13

Phosphine oxide ent-13. [α]25D -33.4 (c 0.76 CHCl3).

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13 14

OOPh2P

N O

O

CO2Et

OOPh2P

O

2) MsCl, Et3NDMAP, CH2Cl2

40oC

OHNH2

1) , 120oC

Oxazoline 14. In a vial was added phosphine oxide 13 (1.95 g, 4.32 mmol) and ethanolamine (1.31 mL, 21.6 mmol). The vial was sealed with a screw cap and heated in an oil bath at 120oC for 2 h. The resulting orange solution was diluted with brine and extracted with EtOAc (2 x 10 mL) and then CH2Cl2 (2 x 10 mL). The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude hydroxyamide (1.94 g, 97%) obtained was used in the next step without further purification. To this hydroxyamide (1.91 g, 4.10 mmol) was added CH2Cl2 (53 mL), Et3N (1.14 mL, 8.21 mmol) and DMAP (5 mg, 0.04 mmol). The solution was cooled to 0oC and methanesulfonyl chloride (0.64 mL, 8.21 mmol) was then added dropwise. The resulting solution was stirred 1 h at 0oC where TLC showed complete disappearance of starting material. Another portion of Et3N (5.15 mL, 36.9 mmol) was then added and the solution was stirred under reflux for 16 h. After cooling the solution, saturated aqueous NH4Cl was added and the mixture was extracted with CH2Cl2 (3 x 50 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (1/1 to 0/1 : hexane/EtOAc) to give oxazoline 14 (1.78 g, 97%) as a white foam. [α]25

D +31.6 (c 0.34 CHCl3). IR (thin film, ν cm-1): 3421, 3058, 2987, 2937, 1669, 1437, 1372, 1250, 1194. 1H NMR: δ 7.79 (1H, dd, J = 7.9, 4.0 Hz), 7.63-7.54 (5H, m), 7.52-7.46 (2H, m), 7.45-7.38 (4H, m), 7.25-7.20 (1H, m), 7.00 (1H, ddd, J = 8.8, 8.2, 1.0 Hz), 6.07 (1H, d, J = 8.2 Hz), 4.55 (1H, d, J = 8.2 Hz), 4.24-4.17 (2H, m), 3.78-3.63 (2H, m), 1.49 (3H, s), 1.26 (3H, s). 13C NMR: δ 164.1, 142.1 (d, JPC = 5.0 Hz), 133.0 (d, JPC = 94.3 Hz), 132.9 (d, JPC = 98.0 Hz), 132.4 (d, JPC = 4.9 Hz), 132.2 (d, JPC = 100.2 Hz), 132.2 (d, JPC = 9.6 Hz), 131.7 (d, JPC = 9.7 Hz), 131.6 (d, JPC = 3.2 Hz), 131.6 (d, JPC = 4.9 Hz), 129.3 (d, JPC = 9.6 Hz), 128.4 (d, JPC = 5.1 Hz), 128.3 (d, JPC = 5.0 Hz), 127.8 (d, JPC = 12.6 Hz), 110.9, 78.9, 76.7, 67.9, 54.4, 26.9, 25.6. 31P NMR: δ 33.3. MS (ESI) (M+H)+: 448.0. HRMS (ESI) (M+H)+ calc’d for C26H27NO4P: 448.1672. Found: 448.1677; (M+Na)+ calc’d for C26H26NO4PNa: 470.1492. Found: 470.1503.

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OOPh2P

N O

O

OOPh2P

N OPhH, 80oC

(EtO)3SiHTi(OiPr)4

14 1

P,N-ligand 1. To a stirred solution of oxazoline 14 (0.56 g, 1.25 mmol) in benzene (63 mL) was added triethoxysilane (1.25 mL, 6.76 mmol) and titanium (IV) isopropoxide (0.20 mL, 0.69 mmol). The solution was stirred under reflux for 4 h. More triethoxysilane (0.23 mL, 1.25 mmol) and titanium (IV) isopropoxide (0.20 mL, 0.31 mmol) were added and the black solution was stirred under reflux for 1 h. After cooling to room temperature, the solvent was stripped off under reduced pressure. The crude product was purified by flash chromatography (8/2 to 1/1 : hexane/EtOAc) to give P,N-ligand 1 (0.26 g, 49%) as a white foam. The product was recrystallized in hexane/Et2O to give white cubic crystals (0.18 g, 32%). [α]25

D -39.0 (c 0.65 CHCl3). IR (thin film, ν cm-1): 3056, 2987, 1669, 1436, 1245, 1216, 1077. 1H NMR: δ 7.68 (1H, dd, J = 6.9, 3.1 Hz), 7.41 (1H, td, J = 7.9, 1.2 Hz), 7.31-7.28 (6H, m), 7.26-7.15 (5H, m), 6.94 (1H, ddd, J = 7.7, 4.1, 1.3 Hz), 6.15 (1H, t, J = 7.9 Hz), 4.52 (1H, d, J = 8.3 Hz), 4.07-4.00 (1H, m), 3.94-3.87 (1H, m), 3.64-3.55 (1H, m), 3.39-3.31 (1H, m), 1.59 (3H, s), 1.53 (3H, s). 13C NMR: δ 164.0, 141.7 (d, JPC = 24.0 Hz), 137.2 (d, JPC = 11.3 Hz), 136.9 (d, JPC = 11.8 Hz), 136.0 (d, JPC = 17.1 Hz), 134.7 (d, JPC = 1.1 Hz), 133.6 (d, JPC = 17.6 Hz), 133.4 (d, JPC = 16.7 Hz), 129.9, 128.8, 128.7, 128.5 (d, JPC = 7.1 Hz), 128.4, 128.3, 127.1 (d, JPC = 6.0 Hz), 111.0, 77.9 (d, JPC = 148.1 Hz), 77.9 (d, JPC = 29.6 Hz), 67.9, 54.3, 27.1, 26.2. 31P NMR: δ -17.7. MS (ESI) (M+H)+: 432.1. HRMS (ESI) (M+H)+ calc’d for C26H27NO3P: 432.1723. Found: 432.1726.

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OOPh2P

N O

(MeCN)2PdCl2CH2Cl2

1-PdCl21

Ph2P PdN

OO

O

Cl Cl

Pd complex 1-PdCl2. To a stirred solution of P,N-ligand X (6.7 mg, 15.5 µmol) in CH2Cl2 (0.13 mL) was added bis(acetonitrile)palladium (II) dichloride (4.0 mg, 15.5 µmol). The solution was stirred 0.1 h at room temperature and then the solvent was stripped off by slow evaporation to give yellow crystals (9.5 mg, 100%). [α]25

D –160.9 (c 0.65 CHCl3). IR (thin film, ν cm-1): 3056, 2991, 2229, 1652, 1436, 1218, 1069. 1H NMR: δ 9.42 (1H, dd, J = 7.6, 2.6 Hz), 8.08 (1H, dd, J = 7.9, 5.0 Hz), 7.67 (1H, t, J = 7.6 Hz), 7.58-7.40 (8H, m), 7.34-7.26 (3H, m), 7.02 (1H, dd, J = 11.0, 8.0 Hz), 4.50-4.41 (1H, m), 4.33-4.27 (1H, m), 3.92 (1H, d, J = 7.8 Hz), 3.69 (1H, q, J = 9.7 Hz), 2.92-2.84 (1H, m), 1.76 (3H, s), 1.71 (3H, s). 13C NMR: δ 166.7, 142.9 (d, JPC = 12.8 Hz), 136.4 (d, JPC = 1.2 Hz), 134.4 (d, JPC = 9.6 Hz), 133.2 (d, JPC = 2.5 Hz), 133.0 (d, JPC = 10.5 Hz), 131.6 (d, JPC = 2.5 Hz), 131.1 (d, JPC = 3.2 Hz), 129.2 (d, JPC = 11.0 Hz), 128.8, 128.3 (d, JPC = 7.5 Hz), 127.9 (d, JPC = 12.0 Hz), 127.2, 126.8 (d, JPC = 8.9 Hz), 112.6, 76.8 (d, JPC = 86.8 Hz), 75.9 (d, JPC = 15.1 Hz), 68.9, 54.6, 26.4, 25.9. 31P NMR: δ 12.7.

Et2(C=O)p-TsOH

PhH, 80oC

11 15

CO2Et

OO

EtEt

OTfOHOTf OH

CO2Et

Ketal 15. To a stirred solution of diol 11 (0.50 g, 1.39 mmol) in benzene (9.3 mL) was added 2-pentanone (1.47 mL, 13.9 mmol) and p-toluenesulfonic acid (26 mg, 0.14 mmol). The solution was stirred at reflux 16 h with a Dean-Stark trap. It was then extracted with Et2O (3 x 10 mL) and saturated aqueous NaHCO3. The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography (9/1 : hexane/EtOAc) to give ketal 15 (0.57 g, 96%) as a light yellow oil. [α]25

D –6.3 (c 0.68 CHCl3). IR (thin film, ν cm-1): 2979, 2944, 2885, 1760, 1424, 1277, 1250, 1216, 1142, 1104. 1H NMR: δ 7.74-7.71 (1H, m), 7.47-7.39 (2H, m), 7.32-7.30 (1H, m), 5.39 (1H, d, J = 8.2 Hz), 4.26 (1H, d, J = 8.2 Hz), 4.26-4.13 (2H, m), 1.90-1.79 (4H, m), 1.22 (3H, t, J = 7.1 Hz), 1.03 (3H, t, J = 6.1 Hz), 1.00 (3H, t, J = 6.1 Hz). 13C NMR: δ 169.1, 147.5, 130.3, 130.1, 128.8, 128.7, 121.3, 120.1, 117.0, 115.9, 81.4, 74.4, 61.7, 29.8, 13.8, 8.1, 7.8. MS (ESI) (M+H)+ calc’d for C17F3H22O7S: 427.0. Found: 427.1.

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CO2Et

OO

EtEt

OTf

CO2Et

OO

EtEt

Ph2PO

15 17

DMSO, 120oC

Ph2P(O)H, i-Pr2NEtPd(OAc)2, dppp

Phosphine oxide 17. To a stirred solution of ketal 15 (0.55 g, 1.29 mmol) in DMSO (26 mL) was added diphenylphosphine oxide (0.56 g, 2.76 mmol), palladium (II) acetate (64 mg, 0.29 mmol), 1,3-bis(diphenylphosphino)propane (0.12 g, 0.29 mmol) and N,N-diisopropylethylamine (0.45 mL, 2.59 mmol). The mixture was stirred at 120oC for 3 h. The resulting dark red mixture was then cooled to room temperature and 5% aqueous HCl (156 mL) was added. The mixture was extracted with CH2Cl2 (3 x 100 mL). The combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (1/1 : hexane/EtOAc) to give phosphine oxide 17 (0.60 g, 97%) as a white-yellow solid. [α]25

D +34.7 (c 0.98 CHCl3). IR (thin film, ν cm-1): 3060, 2977, 1939, 1754, 1437, 1196, 1104. 1H NMR: δ 7.80 (1H, dd, J = 7.3, 4.0 Hz), 7.61-7.53 (5H, m), 7.50-7.35 (6H, m), 7.23-7.19 (1H, m), 6.98 (1H, ddd, J = 13.9, 7.7, 1.1 Hz), 5.91 (1H, dd, J = 8.3, 0.8 Hz), 4.33 (1H, d, J = 8.2 Hz), 4.20-4.09 (2H, m), 1.74-1.68 (2H, qd, J = 7.5, 1.7 Hz), 1.55-1.68 (2H, q, J = 7.6 Hz), 1.14 (3H, t, J = 7.1 Hz), 0.96 (3H, t, J = 7.3 Hz), 0.56 (3H, t, J = 7.4 Hz). 13C NMR: δ 168.9, 142.0 (d, JPC = 6.6 Hz), 133.4 (d, JPC = 103.3 Hz), 133.0 (d, JPC = 12.0 Hz), 132.4 (d, JPC = 100.1 Hz), 132.4 (d, JPC = 105.1 Hz), 132.3 (d, JPC = 2.5 Hz), 132.1 (d, JPC = 9.6 Hz), 131.7 (d, JPC = 2.7 Hz), 131.6 (d, JPC = 2.8 Hz), 131.5 (d, JPC = 9.8 Hz), 129.1 (d, JPC = 9.5 Hz), 128.4 (d, JPC = 4.7 Hz), 128.2 (d, JPC = 4.8 Hz), 127.8 (d, JPC = 12.4 Hz), 114.8, 82.3, 76.7 (d, JPC = 5.7 Hz), 61.1, 29.5, 29.3, 13.8, 7.9, 7.5. 31P NMR: δ 32.8. MS (ESI) (M+H)+ calc’d for C28H32O5P: 479.0. Found: 479.2; (M+Na)+ calc’d for C28H31O5PNa: 501.0. Found: 501.2.

OO

EtEt

Ph2P

N O

O

CO2Et

OO

EtEt

Ph2PO

17 19

2) MsCl, Et3NDMAP, CH2Cl2

40oC

OHNH2

1) , 120oC

Oxazoline 19. In a vial was added phosphine oxide 17 (0.59 g, 1.23 mmol) and ethanolamine (0.37 mL, 6.17 mmol). The vial was sealed and heated in an oil bath at 120oC for 2 h. The resulting orange solution was diluted with brine and extracted with EtOAc (2 x 10 mL) and then CH2Cl2 (2 x 10 mL). The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude hydroxyamide (0.68 g, quant.) obtained was used in the next step without further purification. To this

Page S 12

hydroxyamide was added CH2Cl2 (15 mL), Et3N (0.34 mL, 2.47 mmol) and DMAP (1.5 mg, 12.3 µmol). The solution was cooled to 0oC and methanesulfonyl chloride (0.19 mL, 2.47 mmol) was then added dropwise. The resulting solution was stirred 1 h at 0oC. Another portion of Et3N (1.55 mL, 11.1 mmol) was then added and the solution was stirred under reflux for 16 h. After cooling the solution, saturated aqueous NH4Cl was added and the mixture was extracted with CH2Cl2 (3 x 50 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (1/0 to 95/5 : EtOAc/MeOH) to give oxazoline 19 (0.52 g, 88%) as a white foam. [α]25

D +42.3 (c 1.09 CHCl3). IR (thin film, ν cm-1): 3054, 2973, 2941, 2879, 1671, 1437, 1254, 1084. 1H NMR: δ 7.84 (1H, dd, J = 3.9, 0.7 Hz), 7.62-7.56 (5H, m), 7.53-7.47 (2H, m), 7.45-7.40 (4H, m), 7.25-7.21 (1H, m), 6.99 (1H, ddd, J = 14.0, 7.7, 1.2 Hz), 5.93 (1H, dd, J = 8.4, 0.9 Hz), 4.54 (1H, d, J = 8.4 Hz), 4.32-4.20 (2H, m), 3.80-3.66 (2H, m), 1.80-1.67 (2H, m), 1.62-1.48 (2H, m), 1.00 (3H, t, J = 7.4 Hz), 0.60 (3H, t, J = 7.5 Hz). 13C NMR: δ 164.0, 141.8 (d, JPC = 7.2 Hz), 133.5 (d, JPC = 102.5 Hz), 133.5 (d, JPC = 12.6 Hz), 132.8 (d, JPC = 104.9 Hz), 132.5 (d, JPC = 2.7 Hz), 132.4 (d, JPC = 100.6 Hz), 132.2 (d, JPC = 9.6 Hz), 131.7 (d, JPC = 3.3 Hz), 131.6 (d, JPC = 9.6 Hz), 129.3 (d, JPC = 9.4 Hz), 128.5 (d, JPC = 11.9 Hz), 128.4 (d, JPC = 12.2 Hz), 127.9 (d, JPC = 12.4 Hz), 114.6, 79.4, 76.8, 68.0, 54.4, 29.8, 29.6, 8.0, 7.7. 31P NMR: δ 33.2. MS (ESI) (M+H)+ calc’d for C28H31NO4P: 476.0. Found: 476.0.

Page S 13

OO

EtEt

Ph2P

N O

O

OO

EtEt

Ph2P

N O

(EtO)3SiHTi(OiPr)4

PhH, 80oC

19 2

P,N-ligand 2. To a stirred solution of oxazoline 19 (0.51 g, 1.06 mmol) in benzene (53 mL) was added triethoxysilane (1.06 mL, 5.74 mmol) and titanium (IV) isopropoxide (0.17 mL, 0.58 mmol). The solution was stirred under reflux for 3 h. More triethoxysilane (1.06 mL, 5.74 mmol) and titanium (IV) isopropoxide (0.17 mL, 0.58 mmol) were added and the black solution was stirred under reflux for 1.5 h. After cooling to room temperature, the solvent was stripped off under reduced pressure. The crude product was purified by flash chromatography (9/1 to 1/1 : hexane/EtOAc) to give P,N-ligand 2 (0.24 g, 49%) as a white foam. The product was triturated in hexane to give a white powder (0.14 g, 29%). [α]25

D –36.1 (c 0.78 CHCl3). IR (thin film, ν cm-1): 3056, 2973, 1941, 2881, 1669, 1474, 1436, 1250, 1198, 1173, 1082. 1H NMR: δ 7.72 (1H, ddd, J = 7.9, 4.0, 1.3 Hz), 7.41 (1H, td, J = 7.6, 1.2 Hz), 7.35-7.27 (6H, m), 7.26-7.15 (5H, m), 6.91 (1H, ddd, J = 7.8, 4.1, 1.1 Hz), 6.08 (1H, dd, J = 8.4, 7.5 Hz), 4.51 (1H, d, J = 8.6 Hz), 4.10-4.03 (1H, m), 3.95-3.88 (1H, m), 3.65-3.57 (1H, m), 3.39-3.31 (1H, m), 1.89-1.70 (4H, m), 1.05 (3H, t, J = 7.4 Hz), 0.87 (3H, t, J = 7.5 Hz). 13C NMR: δ 164.0, 141.5 (d, JPC = 23.9 Hz), 137.1 (d, JPC = 11.3 Hz), 136.9 (d, JPC = 11.2 Hz), 136.3 (d, JPC = 15.9 Hz), 134.5 (d, JPC = 1.2 Hz), 133.7 (d, JPC = 10.4 Hz), 133.5 (d, JPC = 9.5 Hz), 129.9, 128.8, 128.7, 128.5, 128.5 (d, JPC = 1.6 Hz), 128.4 (d, JPC = 4.0 Hz), 127.0 (d, JPC = 5.5 Hz), 114.6, 78.9, 77.9 (d, JPC = 29.2 Hz), 67.9, 54.3, 30.1, 30.0, 8.2, 7.9. 31P NMR: δ -14.9. MS (ESI) (M+H)+ calc’d for C28H31NO3P: 460.0. Found: 460.2.

(CH2O)np-TsOH

PhH, 80oC

11 16

CO2

OOOTf

OHOTf OH

CO2Et

Protected diol 16. In a 20 mL vial was added diol 11 (0.30 g, 0.83 mmol) benzene (5.5 mL), paraformaldehyde (0.25 g, 8.32 mmol) and p-toluenesulfonic acid (79 mg, 0.42 mmol). The vial was sealed and the solution was stirred at 100oC for 16 h. It was then extracted with EtOAc (3 x 10 mL) and saturated aqueous NaHCO3. The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography (95/5 to 9/1 : hexane/EtOAc) to give protected diol 16 (0.26 g, 85%) as a clear oil. [α]25

D +22.6 (c 0.73 CHCl3). IR (thin film, ν cm-1): 2985, 2900, 1752, 1424, 1250, 1216, 1140, 1098. 1H NMR: δ 7.58-7.56 (1H, m), 7.44-7.39 (2H, m), 7.33-7.31 (1H, m), 5.45 (1H, s), 5.38 (1H, d, J = 4.9 Hz), 5.23 (1H, s), 4.40 (1H, d, J = 4.9 Hz), 4.41-4.21 (2H, m), 1.27 (3H, t, J = 7.2 Hz). 13C NMR: δ 169.5, 147.0, 131.5, 130.4, 128.8, 121.3, 120.1, 116.9, 97.1, 79.9, 75.6, 61.9, 13.9. MS (ESI) (M+H)+ calc’d for C13F3H14O7S: 371.0. Found: 371.0.

Page S 14

CO2Et

OOOTf

CO2Et

OOPh2P

O

DMSO, 120oC

Ph2P(O)H, i-Pr2NEtPd(OAc)2, dppp

16 18

Phosphine oxide 18. To a stirred solution of protected diol 16 (0.48 g, 1.31 mmol) in DMSO (26 mL) was added diphenylphosphine oxide (0.56 g, 2.78 mmol), palladium (II) acetate (65 mg, 0.29 mmol), 1,3-bis(diphenylphosphino)propane (0.12 g, 0.29 mmol) and N,N-diisopropylethylamine (0.46 mL, 2.61 mmol). The mixture was stirred at 120oC for 3 h. The resulting dark red mixture was then cooled to room temperature and 5% aqueous HCl (157 mL) was added. The mixture was extracted with CH2Cl2 (3 x 100 mL). The combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (1/1 : hexane/EtOAc) to give phosphine oxide 18 (0.58 g, quant.) as a yellow foam. [α]25

D +48.5 (c 0.84 CHCl3). IR (thin film, ν cm-1): 3060, 2983, 2875, 1740, 1437, 1378, 1264, 1189, 1117, 1102, 1038. 1H NMR: δ 7.69 (1H, ddd, J = 7.6, 4.0, 0.5 Hz), 7.60-7.46 (7H, m), 7.43-7.37 (4H, m), 7.23-7.19 (1H, m), 6.99 (1H, ddd, J = 14.0, 7.7, 1.2 Hz), 6.02 (1H, d, J = 4.2 Hz), 5.35 (1H, s), 5.05 (1H, s), 4.47 (1H, d, J = 4.3 Hz), 4.22-4.03 (2H, m), 1.21 (3H, t, J = 7.1 Hz). 13C NMR: δ 169.4, 144.7 (d, JPC = 7.0 Hz), 132.6 (d, JPC = 105.6 Hz), 133.0 (d, JPC = 12.2 Hz), 132.5 (d, JPC = 104.6 Hz), 132.3 (d, JPC = 2.5 Hz), 132.0 (d, JPC = 9.7 Hz), 131.9 (d, JPC = 2.6 Hz), 131.8 (d, JPC = 2.8 Hz), 131.7 (d, JPC = 9.9 Hz), 130.3 (d, JPC = 99.6 Hz), 128.5 (d, JPC = 7.9 Hz), 128.3 (d, JPC = 7.9 Hz), 127.9 (d, JPC = 9.5 Hz), 127.4 (d, JPC = 12.5 Hz), 96.6, 81.3, 77.0 (d, JPC = 5.0 Hz), 61.2, 14.0. 31P NMR: δ 34.0. MS (ESI) (M+H)+ calc’d for C24H24O5P: 423.0. Found: 423.2; (M+Na)+ calc’d for C24H23O5PNa: 445.0. Found: 445.2.

OOPh2P

N O

O

CO2Et

OOPh2P

O

18 20

2) MsCl, Et3NDMAP, CH2Cl2

40oC

OHNH2

1) , 120oC

Oxazoline 20. In a vial was added phosphine oxide 18 (0.57 g, 1.35 mmol) and ethanolamine (0.40 mL, 6.75 mmol). The vial was sealed and heated in an oil bath at 120oC for 2 h. The resulting orange solution was diluted with brine and extracted with EtOAc (2 x 10 mL) and then CH2Cl2 (2 x 10 mL). The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude hydroxyamide (0.63 g, quant.) obtained was used in the next step without further purification. To this hydroxyamide was added CH2Cl2 (17 mL), Et3N (0.38 mL, 2.70 mmol) and DMAP (1.6

Page S 15

mg, 13.5 µmol). The solution was cooled to 0oC and methanesulfonyl chloride (0.21 mL, 2.70 mmol) was then added dropwise. The resulting solution was stirred 1 h at 0oC. Another portion of Et3N (1.70 mL, 12.1 mmol) was then added and the solution was stirred under reflux for 16 h. After cooling the solution, saturated aqueous NH4Cl was added and the mixture was extracted with CH2Cl2 (3 x 25 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (1/0 to 95/5 : EtOAc/MeOH) to give oxazoline 20 (0.50 g, 88%) as a white foam. [α]25

D +83.5 (c 0.63 CHCl3). IR (thin film, ν cm-1): 3058, 2970, 2881, 1671, 1437, 1258, 1183, 1088. 1H NMR: δ 7.72 (1H, dd, J = 7.1, 4.0 Hz), 7.60-7.46 (7H, m), 7.44-7.39 (4H, m), 7.24-7.20 (1H, m), 6.99 (1H, ddd, J = 14.0, 7.7, 1.1 Hz), 6.07 (1H, d, J = 4.8 Hz), 5.37 (1H, s), 5.06 (1H, s), 4.61 (1H, d, J = 4.9 Hz), 4.26-4.16 (2H, m), 3.83-3.67 (2H, m). 13C NMR: δ 164.6, 144.4 (d, JPC = 6.9 Hz), 133.2 (d, JPC = 12.4 Hz), 132.8 (d, JPC = 104.6 Hz), 132.8 (d, JPC = 103.6 Hz), 132.4 (d, JPC = 2.5 Hz), 132.1 (d, JPC = 9.8 Hz), 131.9 (d, JPC = 2.7 Hz), 131.8 (d, JPC = 9.8 Hz), 131.8 (d, JPC = 2.9 Hz), 130.6 (d, JPC = 99.9 Hz), 128.5 (d, JPC = 8.6 Hz), 128.4 (d, JPC = 9.6 Hz), 128.4 (d, JPC = 8.7 Hz), 127.5 (d, JPC = 12.5 Hz), 96.5, 78.0, 77.2 (d, JPC = 5.2 Hz), 67.9, 54.2. 31P NMR: δ 34.3. MS (ESI) (M+H)+ calc’d for C24H23NO4P: 420.0. Found: 420.0.

OOPh2P

N O

O

OOPh2P

N OPhH, 80oC

(EtO)3SiHTi(OiPr)4

20 3

P,N-ligand 3. To a stirred solution of oxazoline 20 (0.44 g, 1.04 mmol) in benzene (52 mL) was added triethoxysilane (1.04 mL, 5.64 mmol) and titanium (IV) isopropoxide (0.17 mL, 0.57 mmol). The solution was stirred under reflux 4 h. More triethoxysilane (0.19 mL, 1.04 mmol) and titanium (IV) isopropoxide (77 µL, 0.26 mmol) were added and the black solution was stirred under reflux 1 h. After cooling to room temperature, the solvent was stripped off under reduced pressure. The crude product was purified by flash chromatography (8/2 to 6/4 : hexane/EtOAc) to give P,N-ligand 3 (0.21 g, 51%) as a white foam. [α]25

D –10.2 (c 1.45 CHCl3). IR (thin film, ν cm-1): 3054, 2971, 2879, 1669, 1478, 1434, 1250, 1162, 1088. 1H NMR: δ 7.62 (1H, ddd, J = 7.8, 4.1, 1.3 Hz), 7.40 (1H, td, J = 7.7, 1.3 Hz), 7.33-7.27 (6H, m), 7.24-7.16 (5H, m), 6.93 (1H, ddd, J = 7.8, 4.2, 1.3 Hz), 6.04 (1H, t, J = 6.5 Hz), 5.41 (1H, s), 5.17 (1H, s), 4.45 (1H, d, J = 6.3 Hz), 4.11-4.01 (2H, m), 3.73-3.65 (1H, m), 3.56-3.47 (1H, m). 13C NMR: δ 164.5, 142.7 (d, JPC = 24.0 Hz), 136.7 (d, JPC = 10.5 Hz), 136.6 (d, JPC = 9.6 Hz), 135.5 (d, JPC = 16.0 Hz), 134.4 (d, JPC = 1.2 Hz), 133.7 (d, JPC = 6.3 Hz), 133.5 (d, JPC = 5.8 Hz), 129.8, 128.7, 128.7, 128.5 (d, JPC = 4.8 Hz), 128.5, 128.4, 126.7 (d, JPC = 5.5 Hz), 96.5 (d, JPC = 2.5 Hz), 78.5 (d, JPC = 28.8 Hz), 77.6, 67.9, 54.2. 31P NMR: δ -17.3. MS (ESI) (M+H)+

calc’d for C24H23NO3P: 404.0. Found: 404.1.

Page S 16

OHNH2

120oCCO2Et

OOPh2P

O

OOPh2P

O NH

O

13 21a

OH

Hydroxyamide 21a. In a vial was added phosphine oxide 13 (0.38 g, 0.83 mmol) and (S)-(+)-2-amino-3-methyl-1-butanol (0.22 g, 2.08 mmol). The vial was sealed and heated in an oil bath at 120oC for 3.5 h. The resulting orange solution was diluted with brine and extracted with EtOAc (2 x 10 mL) and then CH2Cl2 (2 x 10 mL). The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (1/1 to 0/1 : hexane/EtOAc) to give hydroxyamide 21a (0.37 g, 87%) as a white foam. [α]25

D +25.7 (c 0.69 CHCl3). IR (thin film, ν cm-1): 3417, 3362, 3060, 2960, 2935, 2873, 1675, 1526, 1437, 1383, 1183, 1073. 1H NMR: δ 7.80 (1H, dd, J = 7.1, 4.0 Hz), 7.66-7.42 (11H, m), 7.28 (1H, tq, J = 7.7, 1.2 Hz), 7.00 (1H, ddd, J = 14.2, 7.8, 1.1 Hz), 6.90 (1H, d, J = 7.7 Hz), 5.87 (1H, dd, J = 7.4, 1.0 Hz), 5.36 (1H, td, J = 7.2, 2.3 Hz), 4.37 (1H, d, J = 7.4 Hz), 3.91 (1H, dt, J = 11.9, 7.2 Hz), 3.73 (1H, dq, J = 11.8, 3.1 Hz), 3.35 (1H, qd, J = 7.6, 3.1 Hz), 2.08-1.99 (1H, m), 1.50 (3H, s), 1.14 (3H, s), 0.91 (3H, d, J = 6.7 Hz), 0.85 (3H, d, J = 6.8 Hz). 13C NMR: δ 168.5, 142.9 (d, JPC = 6.7 Hz), 133.2 (d, JPC = 12.9 Hz), 132.9 (d, JPC = 2.5 Hz), 132.5 (d, JPC = 104.1 Hz), 132.4 (d, JPC = 9.9 Hz), 132.2 (d, JPC = 2.8 Hz), 132.1 (d, JPC = 2.8 Hz), 131.7 (d, JPC = 10.1 Hz), 131.3 (d, JPC = 107.0 Hz), 131.2 (d, JPC = 101.5 Hz), 129.6 (d, JPC = 9.6 Hz), 128.7 (d, JPC = 6.5 Hz), 128.6 (d, JPC = 6.6 Hz), 128.0 (d, JPC = 12.8 Hz), 110.7, 83.2, 76.6, 62.0, 60.0, 28.4, 26.9, 25.7, 19.8, 19.8. 31P NMR: δ 35.5. MS (ESI) (M+H)+ calc’d for C29H35NO5P: 508.2. Found: 508.4.

OOPh2P

O NH

O

21a

OHCH2Cl2, 40oC

OPh2P

N

O

21

MsCl, Et3N, DMAP

Oxazoline 21. To hydroxyamide 21a (0.36 g, 0.71 mmol) in CH2Cl2 (9.0 mL) was added Et3N (0.50 mL, 3.56 mmol) and DMAP (8.7 mg, 71.1 µmol). The solution was cooled to 0oC and methanesulfonyl chloride (0.14 mL, 1.78 mmol) was then added dropwise. The resulting solution was stirred 1 h at 0oC and 15 h at room temperature. Saturated aqueous NH4Cl was added and the mixture was extracted with CH2Cl2 (3 x 25 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was used immediately in the next step without further purification.

Page S 17

OOPh2P

N O

O

OOPh2P

N OPhH, 80oC

(EtO)3SiHTi(OiPr)4

21 4

P,N-ligand 4. To a stirred solution of oxazoline 21 (0.36 g, 0.74 mmol) in benzene (37 mL) was added triethoxysilane (0.6 mL, 3.24 mmol) and titanium (IV) isopropoxide (0.12 mL, 0.41 mmol). The solution was stirred at reflux 4 h. More triethoxysilane (0.14 mL, 0.74 mmol) and titanium (IV) isopropoxide (54 µL, 0.18 mmol) were added and the black solution was stirred at reflux 1 h. After cooling to room temperature, the solvent was stripped off under reduced pressure. Excess triethoxysilane was distilled off (85oC under vacuum). The crude product was then purified by flash chromatography (95/5 to 6/4 : hexane/EtOAc) to give P,N-ligand 4 (0.16 g, 45%) as a white foam. [α]25

D –65.3 (c 0.94 CHCl3). IR (thin film, ν cm-1): 3054, 2985, 2958, 2933, 2904, 2875, 1673, 1478, 1436, 1382, 1250, 1214, 1165, 1057. 1H NMR: δ 7.65 (1H, ddd, J = 7.9, 4.0, 1.3 Hz), 7.40 (1H, td, J = 7.7, 1.3 Hz), 7.33-7.17 (11H, m), 6.94 (1H, ddd, J = 7.8, 4.1, 1.1 Hz), 6.08 (1H, dd, J = 8.1, 6.6 Hz), 4.61 (1H, d, J = 8.1 Hz), 4.05 (1H, dd, J = 9.5, 8.1 Hz), 3.79 (1H, t, J = 8.7 Hz), 3.77-3.67 (1H, m), 1.65-1.59 (1H, m), 1.56 (3H, s), 1.46 (3H, s), 0.90 (3H, d, J = 6.7 Hz), 0.76 (3H, d, J = 6.7 Hz). 13C NMR: δ 163.2, 141.5 (d, JPC = 23.3 Hz), 137.2 (d, JPC = 11.0 Hz), 136.9 (d, JPC = 11.5 Hz), 136.6 (d, JPC = 17.2 Hz), 134.3 (d, JPC = 1.1 Hz), 133.7 (d, JPC = 3.1 Hz), 133.5 (d, JPC = 2.1 Hz), 129.5, 128.6, 128.6, 128.4 (d, JPC = 3.6 Hz), 128.3 (d, JPC = 3.2 Hz), 128.3, 127.4 (d, JPC = 5.5 Hz), 110.8, 78.2 (d, JPC = 25.8 Hz), 78.1 (d, JPC = 1.1 Hz), 72.4, 70.6 (d, JPC = 1.0 Hz), 32.2, 27.0, 26.0, 19.3, 18.2. 31P NMR: δ -14.1. MS (ESI) (M+H)+ calc’d for C29H33NO3P: 474.0. Found: 474.3.

Page S 18

OOPh2P

N O

(MeCN)2PdCl2CDCl3

4-PdCl24

Ph2P PdN

OO

O

Cl Cl

Pd complex 4-PdCl2. In a drybox, P,N-ligand 4 (5.3 mg, 11.2 µmol) was dissolved in CDCl3 (1.0 mL) and then bis(acetonitrile)palladium (II) dichloride (2.9 mg, 11.2 µmol) was added. The solution was stirred 0.1 h at room temperature and then transferred into a NMR tube. 1H NMR: δ 9.74 (1H, dd, J = 8.9, 2.4 Hz ), 8.11 (1H, dd, J = 7.8, 4.9 Hz ), 7.81-7.59 (2H, m), 7.55-7.50 (4H, m), 7.44-7.37 (4H, m), 7.35-7.26 (2H, m), 6.98 (1H, dd, J = 11.2, 8.8 Hz), 3.98-3.93 (2H, m), 3.08-2.99 (2H, m), 2.84-2.80 (1H, m), 1.89 (3H, s), 1.70 (3H, s), 0.73 (6H, t, J = 6.7 Hz). 31P NMR: δ 16.9.

OHNH2

120oCCO2Et

OOPh2P

O

OOPh2P

O NH

O

13 22a

OH

Hydroxyamide 22a. In a vial was added phosphine oxide 13 (0.43 g, 0.95 mmol) and (R)-(-)-2-amino-3-methyl-1-butanol (0.24 g, 2.36 mmol). The vial was sealed and heated in an oil bath at 120oC for 3.5 h. The resulting orange solution was diluted with brine and extracted with EtOAc (2 x 10 mL) and then CH2Cl2 (2 x 10 mL). The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (1/1 to 0/1 : hexane/EtOAc) to give hydroxyamide 22a (0.41 g, 85%). [α]25

D +71.5 (c 0.62 CHCl3). IR (thin film, ν cm-1): 3411, 3058, 2960, 2933, 2875, 1679, 1526, 1437, 1383, 1225, 1183, 1119, 1071. 1H NMR: δ 7.81 (1H, dd, J = 7.2, 3.9 Hz), 7.66-7.40 (11H, m), 7.26 (1H, tq, J = 7.7, 1.2 Hz), 6.99 (1H, ddd, J = 14.1, 7.8, 1.1 Hz), 6.55 (1H, d, J = 8.4 Hz), 6.03 (1H, d, J = 8.5 Hz), 5.54-5.53 (1H, m), 4.26 (1H, d, J = 8.4 Hz), 3.91-3.86 (1H, m), 3.77-3.71 (1H, m), 3.54 (1H, qu, J = 5.9 Hz), 1.85 (1H, sx, J = 6.9 Hz), 1.51 (3H, s), 1.22 (3H, s), 0.96 (3H, d, J = 6.8 Hz), 0.93 (3H, d, J = 6.8 Hz). 13C NMR: δ 167.5, 141.3 (d, JPC = 6.5 Hz), 133.4 (d, JPC = 13.1 Hz), 132.8 (d, JPC = 103.4 Hz), 132.6 (d, JPC = 2.6 Hz), 132.5 (d, JPC = 10.1 Hz), 132.0 (d, JPC = 107.5 Hz), 132.1 (d, JPC = 2.8 Hz), 131.9 (d, JPC = 2.8 Hz), 131.8 (d, JPC = 9.9 Hz), 131.6 (d, JPC = 102.2 Hz), 129.2 (d, JPC = 9.7 Hz), 128.6 (d, JPC = 9.7 Hz), 128.5 (d, JPC = 10.1 Hz), 127.9 (d, JPC = 13.0 Hz), 109.8, 83.6, 77.1 (d, JPC = 5.4 Hz), 62.3, 57.0, 29.8, 27.0, 26.2, 19.6, 19.0. 31P NMR: δ 35.5. MS (ESI) (M+H)+ calc’d for C29H35NO5P: 508.0. Found: 508.2.

Page S 19

OOPh2P

O NH

O

22a

OHCH2Cl2, 40oC

OOPh2P

N O

O

22

MsCl, Et3N, DMAP

Oxazoline 22. To hydroxyamide 22a (0.40 g, 0.79 mmol) in CH2Cl2 (10.0 mL) was added Et3N (0.55 mL, 3.94 mmol) and DMAP (9.6 mg, 78.8 µmol). The solution was cooled to 0oC and methanesulfonyl chloride (0.15 mL, 1.97 mmol) was then added dropwise. The resulting solution was stirred 1 h at 0oC and 15 h at room temperature. Saturated aqueous NH4Cl was added and the mixture was extracted with CH2Cl2 (3 x 25 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was used immediately in the next step without further purification.

OOPh2P

N O

O

OOPh2P

N OPhH, 80oC

(EtO)3SiHTi(OiPr)4

22 5

P,N-ligand 5. To a stirred solution of oxazoline 22 (0.40 g, 0.82 mmol) in benzene (41 mL) was added triethoxysilane (0.67 mL, 3.60 mmol) and titanium (IV) isopropoxide (0.13 mL, 0.45 mmol). The solution was stirred at reflux 4 h. More triethoxysilane (0.15 mL, 0.82 mmol) and titanium (IV) isopropoxide (60 µL, 0.20 mmol) were added and the black solution was stirred at reflux 1 h. After cooling to room temperature, the solvent was stripped off under reduced pressure. Excess triethoxysilane was distilled off (80oC under vacuum). The crude product was then purified by flash chromatography (95/5 to 6/4 : hexane/EtOAc) to give P,N-ligand 5 (0.21 g, 54%). [α]25

D –7.7 (c 0.66 CHCl3). IR (thin film, ν cm-1): 3056, 2985, 2960, 2933, 1673, 1436, 1382, 1246, 1216, 1165, 1079, 1059. 1H NMR: δ 7.68 (1H, ddd, J = 7.9, 4.1, 1.2 Hz), 7.40 (1H, td, J = 7.6, 1.1 Hz), 7.33-7.26 (6H, m), 7.25-7.17 (5H, m), 6.94 (1H, ddd, J = 7.7, 4.1, 1.2 Hz), 6.13 (1H, t, J = 7.9 Hz), 4.56 (1H, d, J = 8.3 Hz), 3.94 (1H, dd, J = 10.0, 8.3 Hz), 3.78 (1H, t, J = 8.3 Hz), 3.32-3.26 (1H, m), 1.63-1.56 (1H, m), 1.60 (3H, s), 1.52 (3H, s), 0.86 (3H, d, J = 6.7 Hz), 0.76 (3H, d, J = 6.8 Hz). 13C NMR: δ 162.9, 141.8 (d, JPC = 24.0 Hz), 137.2 (d, JPC = 10.4 Hz), 136.9 (d, JPC = 10.3 Hz), 135.8 (d, JPC = 15.2 Hz), 134.8 (d, JPC = 1.4 Hz), 133.5 (d, JPC = 12.0 Hz), 133.3 (d, JPC = 10.9 Hz), 129.9, 128.7, 128.6, 128.4 (d, JPC = 4.8 Hz), 128.4 (d, JPC = 4.5 Hz), 128.2, 127.1 (d, JPC = 5.7 Hz), 110.9, 78.8, 78.0 (d, JPC = 29.6 Hz), 71.9, 70.7, 32.3, 27.0, 26.1, 18.9, 18.4. 31P NMR: δ -17.9. MS (ESI) (M+H)+

calc’d for C29H33NO3P: 474.0. Found: 474.3.

Page S 20

OOPh2P

N O

(MeCN)2PdCl2CDCl3

5-PdCl25

Ph2P PdN

OO

O

Cl Cl

Pd complex 5-PdCl2. In a drybox, P,N-ligand 5 (4.9 mg, 10.3 µmol) was dissolved in CDCl3 (1.0 mL) and then bis(acetonitrile)palladium (II) dichloride (2.7 mg, 10.3 µmol) was added. The solution was stirred 0.1 h at room temperature and then transferred into a NMR tube. 1H NMR: δ 7.86-7.76 (4H, m), 7.67 (1H, dd, J = 8.9, 5.2 Hz), 7.61-7.57 (2H, m), 7.55-7.49 (3H, m), 7.45-7.40 (1H, m), 7.37-7.32 (2H, m), 7.29-7.24 (1H, m), 7.17-7.12 (1H, m), 5.29-5.24 (1H, m), 4.37 (1H, t, J = 9.1 Hz), 4.18 (1H, dd, J = 9.0, 4.8 Hz), 3.97 (1H, d, J = 8.9 Hz), 2.22-2.15 (1H, m), 1.63 (3H, s), 1.59 (3H, s), 0.86 (3H, d, J = 7.0 Hz), 0.10 (3H, d, J = 6.8 Hz). 31P NMR: δ 17.6.

CO2Et

OOPh2P

O

OOPh2P

O NH

O

ent-13 ent23a

OHOHNH2

120oC

Hydroxyamide ent-23a. In a vial was added phosphine oxide ent-13 (0.26 g, 0.95 mmol) and (S)-tert-leucinol (0.34 g, 2.88 mmol). The vial was sealed and heated in an oil bath at 120oC for 5.5 h. The resulting yellow solution was diluted with brine and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (8/2 to 3/7 : hexane/EtOAc) to give hydroxyamide ent-23a (0.28 g, 92%) as a white foam. [α]25

D –53.6 (c 0.68 CHCl3). IR (thin film, ν cm-1): 3417, 3371, 3054, 2960, 2871, 1684, 1522, 1437, 1370, 1239, 1181, 1117, 1071. 1H NMR: δ 7.80 (1H, dd, J = 7.3, 3.9 Hz), 7.66-7.37 (11H, m), 7.23 (1H, m), 6.97 (1H, ddd, J = 14.2, 7.8, 1.2 Hz), 6.50 (1H, d, J = 9.4 Hz), 6.06 (1H, d, J = 8.5 Hz), 5.54 (1H, br s), 4.24 (1H, d, J = 8.5 Hz), 3.93-3.85 (2H, m), 3.56-3.50 (1H, m), 1.51 (3H, s), 1.24 (3H, s), 0.92 (9H, s). 13C NMR: δ 167.4, 141.0 (d, JPC = 6.4 Hz), 132.9 (d, JPC = 97.9 Hz), 132.8 (d, JPC = 86.7 Hz), 132.4 (d, JPC = 10.1 Hz), 131.9 (d, JPC = 2.9 Hz), 131.8 (d, JPC = 90.5 Hz), 131.8 (d, JPC = 2.6 Hz), 131.7 (d, JPC = 9.8 Hz), 130.9 (d, JPC = 102.6 Hz), 128.9 (d, JPC = 9.6 Hz), 128.5 (d, JPC = 12.0 Hz), 128.3 (d, JPC = 12.4 Hz), 127.8 (d, JPC = 13.1 Hz), 109.7, 83.5, 77.1 (d, JPC = 5.6 Hz), 61.4, 59.1, 33.7, 27.0, 26.7, 26.1. 31P NMR: δ 35.3. MS (ESI) (M+H)+ calc’d for C30H37NO5P: 522.6. Found: 522.2.

Page S 21

OOPh2P

O NH

O

ent-23a

OHCH2Cl2, 40oC

OOPh2P

N O

O

MsCl, Et3N, DMAP

ent-23 Oxazoline ent-23. To hydroxyamide ent-23a (0.27 g, 0.51 mmol) in CH2Cl2 (6.4 mL) was added Et3N (0.36 mL, 2.57 mmol) and DMAP (6.3 mg, 51.4 µmol). The solution was cooled to 0oC and methanesulfonyl chloride (0.10 mL, 1.29 mmol) was then added dropwise. The resulting solution was stirred 1 h at 0oC. Another portion of Et3N (0.84 mL, 0.64 mmol) was then added and the solution was stirred under reflux for 16 h. After cooling the solution, saturated aqueous NH4Cl was added and the mixture was extracted with CH2Cl2 (3 x 10 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product (0.24 g, 91%) was used immediately in the next step without further purification.

OOPh2P

N O

O

OOPh2P

N OPhH, 80oC

(EtO)3SiHTi(OiPr)4

ent-23 ent-6

P,N-ligand ent-6. To a stirred solution of oxazoline ent-23 (0.12 g, 0.23 mmol) in benzene (11.5 mL) was added triethoxysilane (0.19 mL, 1.01 mmol) and titanium (IV) isopropoxide (37 µL, 0.13 mmol). The solution was stirred at reflux 3 h. A second portion of triethoxysilane (43 µL, 0.23 mmol) and titanium (IV) isopropoxide (34 µL, 0.12 mmol) were added and the black solution was stirred at reflux 1 h. After cooling to room temperature, the solvent was stripped off under reduced pressure. The crude product was then purified by flash chromatography (1/0 to 85/5 : hexane/EtOAc) to give P,N-ligand ent-6 (23 mg, 27%). [α]25

D –0.1 (c 1.23 CHCl3). IR (thin film, ν cm-1): 3054, 2960, 2904, 2869, 1673, 1478, 1436, 1382, 1248, 1216, 1165, 1079. 1H NMR: δ 7.68 (1H, ddd, J = 7.9, 4.1, 1.2 Hz), 7.40 (1H, td, J = 7.6, 1.1 Hz), 7.33-7.26 (6H, m), 7.25-7.17 (5H, m), 6.94 (1H, ddd, J = 7.7, 4.1, 1.2 Hz), 6.13 (1H, t, J = 7.9 Hz), 4.56 (1H, d, J = 8.3 Hz), 3.94 (1H, dd, J = 10.0, 8.3 Hz), 3.78 (1H, t, J = 8.3 Hz), 3.32-3.26 (1H, m), 1.63-1.56 (1H, m), 1.60 (3H, s), 1.52 (3H, s), 0.86 (3H, d, J = 6.7 Hz), 0.76 (3H, d, J = 6.8 Hz). 13C NMR: δ 163.1, 142.1 (d, JPC = 24.1 Hz), 137.3 (d, JPC = 10.9 Hz), 137.0 (d, JPC = 10.6 Hz), 135.8 (d, JPC = 15.9 Hz), 134.9 (d, JPC = 1.5 Hz), 133.6 (d, JPC = 13.6 Hz), 133.4 (d, JPC = 12.3 Hz), 129.9, 128.7, 128.6, 128.5 (d, JPC = 3.3 Hz), 128.4 (d, JPC = 2.7 Hz), 128.3, 127.2 (d, JPC = 5.7 Hz), 111.0, 78.9 (d, JPC = 1.4 Hz), 78.0 (d, JPC = 29.5 Hz), 75.4, 69.1, 33.3, 27.0, 26.1, 25.9. 31P NMR: δ -16.1. MS (ESI) (M+H)+ calc’d for C30H35NO3P: 488.0. Found: 488.1.

Page S 22

OHNH2

120oCCO2Et

OOPh2P

O

OOPh2P

O NH

O

13 24a

OH

Hydroxyamide 24a. In a vial was added phosphine oxide 13 (0.52 g, 1.15 mmol) and 2-amino-2-methylpropan-1-ol (0.51 g, 5.76 mmol). The vial was sealed and heated in an oil bath at 120oC for 16 h. The resulting orange solution was diluted with brine and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (7/3 to 4/6 : hexane/EtOAc) to give hydroxyamide 24a (0.51 g, 89%). [α]25

D +39.7 (c 0.89 CHCl3). IR (thin film, ν cm-1): 3419, 3357, 3056, 2983, 2931, 2873, 1683, 1522, 1437, 1383, 1219, 1185, 1119, 1069. 1H NMR: δ 7.78 (1H, dd, J = 7.7, 3.9 Hz), 7.68-7.38 (11H, m), 7.26-7.21 (1H, m), 7.00 (1H, ddd, J = 14.1, 8.2, 1.2 Hz), 6.25 (1H, s), 6.05 (1H, d, J = 8.6 Hz), 6.03 (1H, br s), 4.33 (1H, dd, J = 11.6, 5.1 Hz), 4.15 (1H, d, J = 8.5 Hz), 3.07 (1H, dd, J = 11.5, 7.4 Hz), 1.49 (3H, s), 1.26 (3H, s), 1.23 (3H, s), 1.19 (3H, s). 13C NMR: δ 166.8, 141.6 (d, JPC = 6.5 Hz), 133.4 (d, JPC = 13.2 Hz), 132.8 (d, JPC = 103.4 Hz), 132.4 (d, JPC = 10.0 Hz), 132.4 (d, JPC = 2.7 Hz), 131.1 (d, JPC = 107.4 Hz), 131.9 (d, JPC = 2.8 Hz), 131.8 (d, JPC = 2.8 Hz), 131.7 (d, JPC = 9.8 Hz), 130.9 (d, JPC = 102.5 Hz), 129.0 (d, JPC = 9.6 Hz), 128.5 (d, JPC = 12.3 Hz), 128.3 (d, JPC = 12.6 Hz), 127.7 (d, JPC = 12.9 Hz), 109.8, 83.1, 77.2, 76.9 (d, JPC = 5.3 Hz), 65.8, 55.2, 27.0, 25.9, 22.4. 31P NMR: δ 35.0. MS (ESI) (M+H)+ calc’d for C28H33NO5P: 494.2. Found: 494.2.

OOPh2P

O NH

O

24a

OHCH2Cl2, 40oC

OOPh2P

N O

O

24

MsCl, Et3N, DMAP

Oxazoline 24. To hydroxyamide 24a (0.50 g, 1.01 mmol) in CH2Cl2 (12.6 mL) was added Et3N (0.70 mL, 5.04 mmol) and DMAP (12 mg, 0.10 mmol). The solution was cooled to 0oC and methanesulfonyl chloride (0.20 mL, 2.52 mmol) was then added dropwise. The resulting solution was stirred 1 h at 0oC. Another portion of Et3N (1.26 mL, 9.06 mmol) was then added and the solution was stirred under reflux for 16 h. After cooling the solution, saturated aqueous NH4Cl was added and the mixture was extracted with CH2Cl2 (3 x 25 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was then purified by flash

Page S 23

chromatography (9/1 to 3/7 : hexane/EtOAc) to give oxazoline 24 (0.40 g, 84%). [α]25D

+32.5 (c 1.05 CHCl3). IR (thin film, ν cm-1): 3056, 2971, 2935, 1669, 1437, 1382, 1250, 1196. 1H NMR: δ 7.75 (1H, ddd, J = 7.9, 3.9, 0.9 Hz), 7.62-7.38 (11H, m), 7.24-7.19 (1H, m), 6.97 (1H, ddd, J = 13.9, 7.7, 1.1 Hz), 6.01 (1H, d, J = 8.1 Hz), 4.56 (1H, d, J = 8.1 Hz), 4.09 (1H, d, J = 7.6 Hz), 3.93 (1H, d, J = 7.6 Hz), 1.46 (3H, s), 1.26 (3H, s), 1.22 (3H, s), 1.19 (3H, s). 13C NMR: δ 161.6, 141.8 (d, JPC = 6.8 Hz), 133.6 (d, JPC = 102.7 Hz), 133.3 (d, JPC = 12.5 Hz), 132.8 (d, JPC = 105.0 Hz), 132.5 (d, JPC = 100.5 Hz), 132.4 (d, JPC = 2.6 Hz), 132.4, 132.2 (d, JPC = 9.6 Hz), 131.7 (d, JPC = 2.9 Hz), 131.6 (d, JPC = 2.9 Hz), 131.5 (d, JPC = 2.8 Hz), 129.4 (d, JPC = 9.6 Hz), 128.4 (d, JPC = 12.1 Hz), 127.8 (d, JPC = 12.6 Hz), 110.7, 79.1 (d, JPC = 54.2 Hz), 77.2, 76.7 (d, JPC = 5.3 Hz), 67.1, 28.3, 27.8, 26.9, 25.5. 31P NMR: δ 33.0. MS (ESI) (M+H)+ calc’d for C28H31NO4P: 476.2. Found: 476.1.

OOPh2P

N O

OPh2P

PhH, 80oC

(EtO)3SiHTi(OiPr)4

24

P,N-ligand 7. To a stirred solution of oxazoline 24 (0.18 g, 0.37 mmol) in benzene (18.6 mL) was added triethoxysilane (0.19 mL, 1.01 mmol) and titanium (IV) isopropoxide (55 µL, 0.19 mmol). The solution was stirred at reflux 2 h. More triethoxysilane (0.19 mL, 1.01 mmol) and titanium (IV) isopropoxide (55 µL, 0.19 mmol) were added and the black solution was stirred at reflux 2 h. After cooling to room temperature, the solvent was stripped off under reduced pressure. The crude product was then purified by flash chromatography (1/0 to 7/3 : hexane/EtOAc) to give P,N-ligand 7 (0.10 g, 60%). [α]25

D –51.7 (c 1.10 CHCl3). IR (thin film, ν cm-1): 3054, 2970, 2931, 1667, 1436, 1382, 1299, 1250, 1216, 1164, 1077. 1H NMR: δ 7.64 (1H, ddd, J = 7.8, 4.0, 1.2 Hz), 7.39 (1H, tt, J = 8.1, 0.6 Hz), 7.62-7.38 (11H, m), 7.32-7.17 (1H, m), 6.93-6.90 (1H, m), 5.98 (1H, dd, J = 8.1, 6.4 Hz), 4.56 (1H, d, J = 8.1 Hz), 3.81 (2H, dd, J = 18.2, 8.0 Hz), 1.57 (3H, s), 1.43 (3H, s), 1.21 (3H, s), 1.19 (3H, s). 13C NMR: δ 162.0, 141.5 (d, JPC = 23.2 Hz), 136.9 (d, JPC = 10.7 Hz), 136.6 (d, JPC = 11.3 Hz), 136.4 (d, JPC = 16.5 Hz), 134.2 (d, JPC = 1.1 Hz), 133.7 (d, JPC = 4.2 Hz), 133.5 (d, JPC = 5.2 Hz), 129.7, 128.7, 128.5 (d, JPC = 3.6 Hz), 128.4, 128.4 (d, JPC = 1.9 Hz), 127.2 (d, JPC = 5.5 Hz), 110.9, 79.4 (d, JPC = 1.4 Hz), 78.5, 78.2 (d, JPC = 26.2 Hz), 77.2, 67.2, 28.2, 27.9, 27.0, 25.9. 31P NMR: δ -14.1. MS (ESI) (M+H)+ calc’d for C28H31NO3P: 460.2. Found: 460.3.

Page S 24

OHNH2

120oCCO2Et

OOPh2P

O

OOPh2P

O NH

O

13 25a

OH

Hydroxyamide 25a. In a vial was added phosphine oxide 13 (0.37 g, 0.82 mmol) and 1-amino-1-cyclopentanemethanol (0.38 g, 3.29 mmol). The vial was sealed and heated in an oil bath at 120oC for 18 h. The resulting orange solution was diluted with brine and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (8/2 to 4/6 : hexane/EtOAc) to give hydroxyamide 25a (0.36 g, 84%). [α]25

D +23.3 (c 0.78 CHCl3). IR (thin film, ν cm-1): 3419, 3363, 3058, 2985, 2954, 2871, 1677, 1522, 1437, 1382, 1219, 1185, 1117, 1069. 1H NMR: δ 7.77 (1H, ddd, J = 7.9, 4.0, 0.9 Hz), 7.67-7.38 (11H, m), 7.26-7.21 (1H, m), 6.99 (1H, ddd, J = 14.1, 7.8, 1.0 Hz), 6.37 (1H, s), 6.16-6.12 (1H, m), 6.03 (1H, d, J = 8.5 Hz), 4.32 (1H, dd, J = 11.7, 5.9 Hz), 4.16 (1H, d, J = 8.5 Hz), 3.14 (1H, dd, J = 11.6, 7.4 Hz), 2.02-1.95 (2H, m), 1.69-1.53 (8H, m), 1.49 (3H, s), 1.18 (3H, s). 13C NMR: δ 166.9, 141.4 (d, JPC = 6.6 Hz), 133.3 (d, JPC = 13.1 Hz), 132.8 (d, JPC = 103.4 Hz), 132.4 (d, JPC = 10.0 Hz), 132.4 (d, JPC = 2.6 Hz), 132.0 (d, JPC = 107.4 Hz), 131.9 (d, JPC = 2.8 Hz), 131.8 (d, JPC = 2.8 Hz), 131.7 (d, JPC = 9.8 Hz), 131.0 (d, JPC = 102.5 Hz), 129.1 (d, JPC = 9.6 Hz), 128.5 (d, JPC = 12.1 Hz), 128.3 (d, JPC = 12.5 Hz), 127.8 (d, JPC = 13.1 Hz), 109.7, 83.1, 77.2, 76.9 (d, JPC = 5.3 Hz), 66.0, 64.6, 37.4, 33.6, 27.0, 26.0, 24.3, 23.7. 31P NMR: δ 34.9. MS (ESI) (M+H)+ calc’d for C30H35NO5P: 520.2. Found: 520.3.

OOPh2P

O NH

O

25a

OHCH2Cl2, 40oC

OOPh2P

N O

O

25

MsCl, Et3N, DMAP

Oxazoline 25. To hydroxyamide 25a (0.35 g, 0.67 mmol) in CH2Cl2 (8.3 mL) was added Et3N (0.46 mL, 3.34 mmol) and DMAP (8.2 mg, 66.8 µmol). The solution was cooled to 0oC and methanesulfonyl chloride (0.13 mL, 1.67 mmol) was then added dropwise. The resulting solution was stirred 1 h at 0oC. Another portion of Et3N (0.84 mL, 6.01 mmol) was then added and the solution was stirred under reflux for 16 h. After cooling the solution, saturated aqueous NH4Cl was added and the mixture was extracted with CH2Cl2 (3 x 25 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was used immediately in the next step without further purification.

Page S 25

OOPh2P

N O

O

OOPh2P

N OPhH, 80oC

(EtO)3SiHTi(OiPr)4

25 8

P,N-ligand 8. To a stirred solution of oxazoline 25 (0.28 g, 0.55 mmol) in benzene (28 mL) was added triethoxysilane (0.41 mL, 2.22 mmol) and titanium (IV) isopropoxide (90 µL, 0.30 mmol). The solution was stirred at reflux 3 h. More triethoxysilane (0.14 mL, 0.78 mmol) and titanium (IV) isopropoxide (90 µL, 0.30 mmol) were added and the black solution was stirred at reflux 1 h. After cooling to room temperature, the solvent was stripped off under reduced pressure. The crude product was then purified by flash chromatography (1/0 to 8/2 : hexane/EtOAc) to give P,N-ligand 8 (0.12 g, 45%). [α]25

D –48.1 (c 0.99 CHCl3). IR (thin film, ν cm-1): 3054, 2985, 2956, 2871, 1665, 1478, 1434, 1382, 1248, 1214, 1164, 1075, 1059. 1H NMR: δ 7.65 (1H, ddd, J = 7.8, 3.9, 1.0 Hz), 7.39 (1H, td, J = 7.3, 0.9 Hz), 7.32-7.16 (11H, m), 6.91 (1H, ddd, J = 7.7, 4.1, 1.3 Hz), 6.02 (1H, dd, J = 8.1, 6.3 Hz), 4.57 (1H, d, J = 8.1 Hz), 3.94 (2H, s), 1.84-1.51 (4H, m), 1.57 (3H, s), 1.56-1.42 (4H, m), 1.45 (3H, s). 13C NMR: δ 161.8, 141.5 (d, JPC = 23.7 Hz), 136.9 (d, JPC = 11.3 Hz), 136.6 (d, JPC = 11.2 Hz), 136.3 (d, JPC = 16.0 Hz), 134.1, 133.6 (d, JPC = 2.4 Hz), 133.5 (d, JPC = 3.7 Hz), 129.6, 128.6, 128.6, 128.5 (d, JPC = 2.5 Hz), 128.4 (d, JPC = 1.8 Hz), 128.4, 127.1 (d, JPC = 5.3 Hz), 110.8, 78.8 (d, JPC = 1.5 Hz), 78.5, 78.1 (d, JPC = 26.4 Hz), 77.3, 40.0, 39.3, 26.9, 26.0, 24.4, 24.3. 31P NMR: δ -14.1. MS (ESI) (M+H)+ calc’d for C30H33NO3P: 486.2. Found: 486.3.

OHNH2

130oCCO2Et

OOPh2P

O

OOPh2P

O NH

O

13 26a

OH

PhPh

PhPh

Hydroxyamide 26a. In a vial was added phosphine oxide 13 (0.17 g, 0.38 mmol) and 2,2-diphenylglycinol (0.37 g, 1.72 mmol). The vial was sealed and heated in an oil bath at 130oC for 24 h. The resulting orange solution was diluted with brine and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product (0.14 g, 61%, 100% based on recovered starting material) was used immediately in the next step without further purification.

Page S 26

OOPh2P

O NH

O

26a

OHCH2Cl2, 40oC

OOPh2P

N O

O

26

MsCl, Et3N, DMAP

PhPh

Ph

Ph

Oxazoline 26. To hydroxyamide 26a (0.13 g, 0.22 mmol) in CH2Cl2 (2.7 mL) was added Et3N (0.15 mL, 1.09 mmol) and DMAP (2.7 mg, 21.7 µmol). The solution was cooled to 0oC and methanesulfonyl chloride (42 µL, 0.54 mmol) was then added dropwise. The resulting solution was stirred 1 h at 0oC. Another portion of Et3N (0.27 mL, 1.95 mmol) was then added and the solution was stirred under reflux for 16 h. After cooling the solution, saturated aqueous NH4Cl was added and the mixture was extracted with CH2Cl2 (3 x 25 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product (0.12 g, 94%) was used immediately in the next step without further purification.

OOPh2P

N O

O

26

PhPh

OOPh2P

N O

9

PhPh

PhH, 80oC

(EtO)3SiHTi(OiPr)4

P,N-ligand 9. To a stirred solution of oxazoline 26 (0.12 g, 0.20 mmol) in benzene (10 mL) was added triethoxysilane (0.17 mL, 0.90 mmol) and titanium (IV) isopropoxide (33 µL, 0.11 mmol). The solution was stirred at reflux 3 h. More triethoxysilane (38 µL, 0.20 mmol) and titanium (IV) isopropoxide (30 µL, 0.10 mmol) were added and the black solution was stirred at reflux 1 h. After cooling to room temperature, the solvent was stripped off under reduced pressure. The crude product was then purified by flash chromatography (1/0 to 9/1 : hexane/EtOAc) to give P,N-ligand 9 (77 mg, 65%). [α]25

D –36.7 (c 0.73 CHCl3). IR (thin film, ν cm-1): 3056, 2987, 2933, 1671, 1492, 1474, 1436, 1382, 1246, 1216, 1164, 1079, 1059. 1H NMR: δ 7.67 (1H, ddd, J = 7.8, 4.0, 1.1 Hz), 7.41 (1H, td, J = 7.5, 1.0 Hz), 7.32-7.14 (19H, m), 6.95 (2H, td, J = 7.8, 1.0 Hz), 6.86 (1H, ddd, J = 7.7, 4.2, 1.3 Hz), 6.04 (1H, dd, J = 7.9, 5.8 Hz), 4.82 (1H, d, J = 7.9 Hz), 4.75 (2H, s), 1.58 (3H, s), 1.41 (3H, s). 13C NMR: δ 163.2, 145.7 (d, JPC = 14.5 Hz), 140.9 (d, JPC = 22.1 Hz), 137.0 (d, JPC = 10.8 Hz), 136.7 (d, JPC = 17.6 Hz), 136.2 (d, JPC = 11.1 Hz), 133.9 (d, JPC = 19.8 Hz), 133.9, 133.6 (d, JPC = 19.9 Hz), 129.5, 128.8, 128.6, 128.5, 128.4, 128.4, 128.3, 128.3 (d, JPC = 2.0 Hz), 128.3, 127.4 (d, JPC = 5.2 Hz), 127.0, 126.9, 126.7, 126.5, 111.2, 80.0 (d, JPC = 2.3 Hz), 79.1, 78.6 (d, JPC = 23.9 Hz), 78.3 (d, JPC = 1.6 Hz), 27.0, 25.9. 31P NMR: δ -13.1. MS (ESI) (M+H)+ calc’d for C38H35NO3P: 584.7. Found: 584.3.

Page S 27

[(allyl)PdCl]2, BSA, KOAc, CH2Cl2

CO2MeCO2Me

ligand,

Ph Ph

OAc

Ph Ph

CO2MeMeO2C

27 28

Representative procedure for enantioselective Pd-catalyzed allylic substitution.

An oven-dried vial was charged with allyl palladium (II) chloride dimer (3.9 mg, 10.7 µmol), chiral P,N-ligand (19.4 µmol), potassium acetate (2 mg) and CH2Cl2 (1.2 mL) under an inert atmosphere of argon in a drybox. The reaction mixture was stirred at room temperature for 0.5 h, then 1,3-diphenylprop-2-en-1-yl acetate 27 (0.16 g, 0.65 mmol) was added and the mixture was stirred for an additional 0.25 h. Dimethyl malonate (0.22 mL, 1.94 mmol) was added to the reaction mixture at this temperature followed by N,O-bis(trimethylsilyl)acetamide (0.48 mL, 1.94 mmol). The vial was sealed with a screw-cap and removed from the drybox, where the solution was allowed to stir for 2 h at room temperature. After removal of the solvent under reduced pressure, the crude product was purified by flash chromatography (95/5 : hexane/EtOAc) to yield 28 (0.19 g, 88%) as a colorless oil. [α]25

D +17.1 (c 1.09 CHCl3), 97.4% ee. IR (thin film, ν cm-1): 3027, 2952, 1760, 1737, 1495, 1453, 1434, 1316, 1248, 1158. 1H NMR: δ 7.33-7.17 (10H, m), 6.48 (1H, d, J = 15.8 Hz), 6.33 (1H, dd, J = 15.7, 8.6 Hz), 4.27 (1H, dd, J = 10.5, 8.6 Hz), 3.96 (1H, d, J = 10.9 Hz), 3.70 (3H, s), 3.51 (3H, s). 13C NMR: δ 168.1, 167.7, 140.2, 136.8, 131.8, 129.1, 128.7, 128.4, 127.8, 127.5, 127.1, 126.3, 57.6, 52.5, 52.4, 49.1. MS (ESI) (M+Na)+: 347.2. HRMS (ESI) (M+Na)+ calc’d for C20H20O4Na: 347.126. Found: 347.123. Chiral HPLC (Chiralcel OD-H, Daicel, 1% i-PrOH in hexane, 1.0 mL/min, wavelength: 220 nm) analysis of the product:

Allylic substitution with chiral ligand 5

Racemic allylic substitution

Page S 28

O O

O

THF

Oligand, Pd2(dba)3

29 30

Representative procedure for enantioselective Pd-catalyzed Tsuji allylation.

An oven-dried vial was charged with tris(dibenzylideneacetone) dipalladium (0) (5.6 mg, 6.1 µmol), chiral P,N-ligand (19.6 µmol) and THF (7.4 mL) under an inert atmosphere of argon in a drybox. The reaction mixture was stirred at room temperature for 0.5 h, then enol carbonate 29 (69 mg, 0.28 mmol) was added. The vial was sealed with a screw-cap and removed from the drybox, where the solution was allowed to stir for 2 h at room temperature. After removal of the solvent under reduced pressure, the crude product was purified by flash chromatography (1:0 to 98/2 : hexane/EtOAc) to yield 30 (53 mg, 94%) as a colorless oil. IR (thin film, ν cm-1): 3076, 2966, 2929, 2856, 1683, 1640, 1602, 1455, 1221. 1H NMR: δ 8.02 (1H, dd, J = 7.9, 1.4 Hz), 7.43 (1H, td, J = 7.5, 1.5 Hz), 7.30-7.25 (1H, m), 7.19 (1H, dd, J = 7.7, 0.5 Hz), 5.82-5.71 (1H, m), 5.07 (1H, t, J = 1.1 Hz), 5.05-5.02 (1H, m), 2.97-2.93 (2H, m), 2.44 (1H, dd, J = 13.8, 7.3 Hz), 2.25 (1H, ddt, J = 13.8, 7.5, 1.1 Hz), 2.09-2.02 (1H, m), 1.91-1.85 (1H, m), 1.17 (3H, s). 13C NMR: δ 201.9, 143.3, 133.9, 133.0, 131.6, 128.6, 128.0, 126.6, 118.1, 44.6, 41.1, 33.3, 25.3, 21.9. MS (ESI) (M+Na)+: 223.2. HRMS (ESI) (M+Na)+ calc’d for C14H16ONa: 223.110. Found: 223.112. Chiral HPLC (Chiralcel OD-H, Daicel, hexane, 0.7 mL/min, wavelength: 254 nm) analysis of the product:

Tsuji allylation with chiral ligand 5

Racemic Tsuji allylation