1.1.general experimantal methods · web viewanalytical chiral separations were performed on an...

Supporting Information - Novel biferrocene-based phosphoramidite ligands the combination of a rather unexplored chiral backbone and a privileged ligand scaffold

W Kimpea P Janssensa K Berta S Wackensa J L Goemana and J Van der Eyckena

a Laboratory for Organic and Bioorganic Synthesis Department of Organic and Macromolecular Chemistry Ghent University Krijgslaan 281 (S4) B-9000 Ghent Belgium E-mail JohanVanderEyckenUGentbe Fax +32-9-264-49-98Corresponding author

Supporting Information

11 General Experimantal Methods2

12 Synthesis of (SpSp)-[11rsquo-bifferrocenyl]-22rsquo-dicarboxaldehyde (SpSp-9)2

121 Metallic copper based synthesis of (SpSp)-[11rsquo-bifferrocenyl]-22rsquo-dicarboxaldehyde (SpSp-9) 2

122 CuTC based synthesis of (SpSp)-[11rsquo-bifferrocenyl]-22rsquo-dicarboxaldehyde (SpSp-9) 3

13 Synthesis of (SpSp)-N-benzyl-35-dihydro-4H-diferrocenyl-[ce]-azepine (SpSp-14)9

14 Synthesis of (SpSp)-N-4-methoxybenzyl-35-dihydro-4H-diferrocenyl-[ce]-azepine (SpSp-15) 12

15 Synthesis of (SpSp)-N-allyl-35-dihydro-4H-diferrocenyl-[ce]-azepine (SpSp-10)15

16 Synthesis of (SpSp)-N-H-35-dihydro-4H-diferrocenyl-[ce]-azepine (SpSp-11)18

17 Synthesis of biphenol-based phosphoramidite ligand (6a)21

18 Synthesis of (R)-binol-based phosphoramidite ligand (6b)25

19 Synthesis of (S)-binol-based phosphoramidite ligand (6c)29

110 Synthesis of Methyl Z-2-acetamido-3-phenylacrylate (12)33

111 Rhodium(I)-catalyzed asymmetric hydrogenations of 12 using novel ligands36

11 General Experimantal Methods

Unless otherwise stated all reagents were obtained commercially and used without further purification All reactions were carried out under an argon atmosphere in dry solvents under anhydrous conditions unless otherwise noted Dichloroethane Et3N and DIPEA were dried via distillation over CaH2 Toluene was dried via distillation over sodium with benzophenone as indicator Other anhydrous solvents were purchased as such Analytical TLC was performed by using Machery-Nagel SIL G-25 UV254 plates Flash chromatography was carried out with Rocc silica gel (0040-0063 mm) 1H NMR and 13C NMR spectra were recorded with a Bruker avance 300 or a Bruker Avance 400 or a Bruker AM 500 spectrometer as indicated with chemical shifts reported in ppm relative to TMS by using the residual solvent signal as a standard and relative to 85 aqueous phosphoric acid for 31P NMR spectra IR spectra were recorded with a Perkin-Elmer SPECTRUM-1000 FTIR spectrometer with a Pike Miracle Horizontal Attenuated Total Reflectance (HATR) module ESI-MS was performed on an Agilent 1100 series with a single quadrupole MS detector G1946C (type VL) equipped with an API-ESI source High Resolution Mass Spectrometry (HRMS) was performed on an Agilent 1100 series connected to a 6220A TOF-MS detector equipped with an APCI-ESI multimode source or a Kratos MS50TC mass spectrometer (EI) For all MS-analysis the standard solvent was a 5050 mixture of MeOH5 mM aqueous NH4OAc and a sample volume of 5microL was injected LC-MS analyses were performed on an Agilent 1100 series HPLC connected to a UV-DAD detector and a single quadrupole MS detector G1946C (type VL) equipped with an API-ESI source by using a Phenomenex Kinetex C18 column (150 x 46 mm 5 microm particle size) All measurements were performed at 35degC a flow rate of 1 mLmin and sample volume of 15 microL was injected Mili-Q water and HPLC quality grade CH3CN were used Analytical chiral separations were performed on an Agilent 1100 series HPLC system using a Chiralcel OD-H column (250 x 46 mm 5 microm particle size) or a Chiralpak AS-H column (250 x 46 mm 5 microm particle size) connected to a UV-DAD detector All measurements were performed at 35degC a flow rate of 1 mLmin and a sample volume of 20 microL HPLC quality grade solvents were used for all measurements Optical rotations were measured using a Perkin-Elmer 214 polarimeter at 589 nm

12 Synthesis of (SpSp)-[11rsquo-bifferrocenyl]-22rsquo-dicarboxaldehyde (SpSp-9)

121 Metallic copper based synthesis of (SpSp)-[11rsquo-bifferrocenyl]-22rsquo-dicarboxaldehyde (SpSp-9)

An oven-dried 50 mL round-bottom flask was charged with (Sp)-8 (2610 g 768 mmol) Metallic copper (1950 g 3071 mmol 4 eq) was carefully added in such way that all of the starting material was covered with copper A heavy egg-shaped stirring bar was carefully added and the reaction flask was wrapped in aluminum foil The reaction was stirred overnight at 105degC The crude reaction mixture was taken up in CH2Cl2 and filtered over Celite while the filtrate was collected in a round-bottom flask which was wrapped in aluminum foil The solvent was removed under reduced pressure

and the resulting residue was purified by flash chromatography1 (gradient n-hexaneEtOAC 82 to 64) affording (SpSp)-9 with a yield of 668 as a red solid

122 CuTC based synthesis of (SpSp)-[11rsquo-bifferrocenyl]-22rsquo-dicarboxaldehyde (SpSp-9)

An oven-dried 5 mL round-bottom flask was charged with a magnetic stirring bar (Sp)-8 (68 mg 020 mmol) and CuTC (114 mg 060 mmol 3 eq) Anhydrous NMP (10 mL) was added and the reaction flask was wrapped in aluminum foil The reaction mixture was heated to 70degC and stirred overnight Then the reaction mixture was allowed to cool to room temperature diluted with Et2O and filtered over Celite Et2O was removed under reduced pressure The residu was taken up in Et 2O (10 mL) and washed 3 times with water (10 mL) The organic phase was dried over anhydrous MgSO4 and filtered off Et2O was removed under reduced pressure and the resulting residue was purified by flash chromatography (gradient n-hexaneEtOAC 82 to 64) affording (SpSp)-9 with a yield of 590 as a red solid

Rf ((SpSp)-9) (n-hexaneEtOAc 73) 025Rf ((RpSp)-9 meso-form) (n-hexaneEtOAc 73) 0401H-NMR (500 MHz CDCl3) δ = 431 (s 10H) 474 (dd J = 28 Hz J = 24 Hz 2H) 494 (dd J = 24 Hz J = 16 2H) 495 (dd J = 28 Hz J = 16 2H) 994 (s 2H) ppm13C-NMR (125 MHz CDCl3) δ = 688 (CH x2) 710 (CH x10) 719 (CH x2) 766 (CH x2) 786 (C x2) 853 (C x2) 1922 (CH x2) ppmIR (HATR) υmax = 3921 3561 3315 3101 3009 2941 2840 2778 2764 1661 1652 1426 1409 1395 1289 1208 1106 998 990 825 774 733 679 cm-1HRMS (ESI) calculated for C22H19Fe2O2 [M+H]+ 4270078 found 4270079 Optical rotation [ α ]D

20=iquest -257deg (c 01 CH2Cl2)Mp 175-176degC

1Because 9 is light sensitive the column was wrapped in aluminum foil as well First a mixed fraction of ferrocenecarboxaldehyde 7 and α-iodoferrocenecarboxaldehyde (Sp)-8 was collected The polarity of the eluent system was raised to n-hexaneEtOAC 73 and the meso-form (RpSp)-9 was collected The polarity of the eluent system was raised to n-hexaneEtOAC 64 and (SpSp)-[11rsquo-bifferrocenyl]-22rsquo-dicarboxaldehyde (SpSp)-9 was collected in a round bottom flask which was wrapped in aluminum foil

Reversed phase HPLC-MS conditions Agilent1100 series connected to a UV-DAD detector (and a single quadrupole MS detector) Phenomenex Kinetex C18 column (150 x 46 mm 150 microm particle size) H2OCH3CN eluent system 15 ml flow rate 35degC operating temperature and injection of a sample volume of 15 microl of a 1 mgmL sample concentration

Chiral HPLC conditionsAgilent1100 series connected to a UV-DAD Chiralpak AS-H column (250 x 46 mm 150 microm particle size) n-hexaneEtOH 8020 eluent system 10 ml flow rate 35degC operating temperature and injection of a sample volume of 20 microl of a 1 mgmL sample concentration

Figure 1 HPLC Chromatogram of biferrocene-based isomers of 9 after homocoupling of racemic (Sp)-8 (after work-up and before silicagel purification) A ratio almost equal to 21 is observed for the three

isomomers (RpRp)-9(SpSp)-9 (6131 min) and (RpSp)-9 (6196 min)

Figure 2 Chromatogram chiral HPLC of biferrocene-based isomers of 9 after homocoupling of racemic (Sp)-8 (after work-up and before silicagel purification) A ratio almost equal to 111 is

observed for the three isomomers (RpSp)-9 (12675 min) (SpSp)-9 (14275 min) (RpRp)-9 (15889 min)

6131 min(RpRp)-9 and (SpSp)-9

6196 min(RpSp)-9 meso-form


14275 min(SpSp)-9

15889 min(RpRp)-9

Figure 3 HPLC chromatogram after homocoupling of (Sp)-8 with an enantiomeric excess of 68 After purification via silicagel chromatography a single peak at 6131 min is observed There is no

signal corresponding to meso-compound (RpSp)-9 detected

Figure 4 Chromatogram of chiral HPLC analysis after homocoupling of (Sp)-8 with an enantiomeric excess of 68 After purificataion via silicagel chromatography only one signal is observed at 14719

min Consequently (SpSp)-dialdehyde 9 could be obtained as a single enantiomer

6131 min

14719 min(SpSp)-9

Figure 5 HPLC chromatogram after homocoupling of (Sp)-8 with an enantiomeric excess of 68 After purification via silicagel chromatography a major 6195 min is observed corresponding to meso-compound (RpSp)-9 A (very) small peak at 6132 min is detected corresponding to its diastereomer(s)

(ratio of meso-compound (RpSp)-9 to its diastereomer(s) gt 99)

Figure 6 Chromatogram of chiral HPLC analysis showing one signal corresponding to meso-compound (RpSp)-9 Signals corresponding to its diastereomers (RpRp)-9 and (SpSp)-9 are too small

and can therefore be ignored

6195 min(RpSp)-9 meso form


13 Synthesis of (SpSp)-N-benzyl-35-dihydro-4H-diferrocenyl-[ce]-azepine (SpSp-14)

An oven-dried 25 mL two-neck round-bottom flask was charged with a magnetic stirring bar (SpSp)-9 (118 mg 028 mmol) Freshly distilled dichloroethane (80 mL) was added followed by a solution of benzylamine in dichloroethane (13 M 850 microL 11 mmol 4 eq) The reaction mixture was stirred for 5 min at room temperature and NaBH3CN (609 mg 969 mmol 35 eq) and anhydrous K2CO3 (153 mg 111 mmol 4 eq) were added The reaction was stirred overnight at room temperature and quenched with a saturated solution of NaHCO3 (30 mL) The aqueous phase was extracted 3 times with CH2Cl2 (30 mL) The combined organic phases were dried over anhydrous MgSO4 and filtered off The solvents were removed under reduced pressure and the resulting residue was purified by flash chromatography (n-hexaneEtOAcEt3N 8202) affording (SpSp)-14 with a yield of 799

Rf (n-hexaneEtOAc 73) 0141H-NMR (500 MHz CDCl3) δ = 372 (d J = 150 Hz 2H) 388-389 (m 2H) 389 (d J = 150 Hz 2H) 395 (s 10H) 399-400 (m 2H) 411 (dd J = 24 Hz J = 22 Hz 2H) 439 (dd J = 24 Hz J = 14 Hz 2H) 736 (m 5H) ppm13C-NMR (125 MHz CDCl3) δ = 564 (CH2 x2) 604 (CH2) 658 (CH x2) 663 (CH x2) 677 (CH x2) 699 (CH x10) 826 (C x2) 845 (C x2) 1270 (CH) 1283 (CH) 1289 (CH) 1393 (C) ppmIR (HATR) υmax = 3920 3087 2923 2852 1731 1493 1453 1357 1265 1130 1104 1028 999 815 804 734 698 cm-1HRMS (ESI) calculated for C29H28Fe2N [M+H]+ 5020915 found 5020917Optical rotation [ α ]D

20=iquest -508deg (c 12 CHCl3)

14 Synthesis of (SpSp)-N-4-methoxybenzyl-35-dihydro-4H-diferrocenyl-[ce]-azepine (SpSp-15)

An oven-dried 25 mL two-neck round-bottom flask was charged with a magnetic stirring bar (SpSp)-9 (118 mg 028 mmol) Freshly distilled dichloroethane (80 mL) was added followed by a solution of para-methoxybenzylamine in dichloroethane (13 M 850 microL 11 mmol 4 eq) The reaction mixture was stirred for 5 min at room temperature and NaBH3CN (609 mg 969 mmol 35 eq) and anhydrous K2CO3 (153 mg 111 mmol 4 eq) were added The reaction was stirred overnight at room temperature and quenched with a saturated solution of NaHCO3 (30 mL) The aqueous phase was extracted 3 times with CH2Cl2 (30 mL) The combined organic phases were dried over anhydrous MgSO4 and filtered off The solvents were removed under reduced pressure and the resulting residue was purified by flash chromatography (n-hexaneEtOAcEt3N 8202) affording (SpSp)-15 with a yield of 882

Rf (n-hexaneEtOAc 73) 0141H-NMR (500 MHz CDCl3) δ = 370 (d J = 149 Hz 2H) 380-382 (m 2H) 383 (s 3H) 386 (d J = 149 Hz 2H) 395 (s 10H) 398-401 (m 2H) 410 (dd J = 24 Hz J = 22 Hz 2H) 438 (dd J = 22 Hz J = 14 Hz 2H) 689 (br d J = 85 Hz 2H) 73 (br d J = 85 Hz 2H) ppm13C-NMR (125 MHz CDCl3) δ = 553 (CH3) 562 (CH2 x2) 598 (CH2) 658 (CH x2) 662 (CH x2) 677 (CH x2) 700 (CH x10) 826 (C x2) 845 (C x2) 1137 (CH) 1301 (CH) 1587 (C) ppm 1C not observedIR (HATR) υmax = 3916 3090 2925 2833 1610 1584 1455 1440 1357 1300 1170 1130 1104 1031 999 814 733 703 cm-1HRMS (ESI) calculated for C30H30Fe2NO [M+H]+ 5321021 found 5321032Optical rotation [ α ]D


15 Synthesis of (SpSp)-N-allyl-35-dihydro-4H-diferrocenyl-[ce]-azepine (SpSp-10)

An oven-dried 25 mL two-neck round-bottom flask was charged with a magnetic stirring bar (SpSp)-9 (118 mg 028 mmol) Freshly distilled dichloroethane (80 mL) was added followed by a solution of allylamine in dichloroethane (13 M 850 microL 11 mmol 4 eq) The reaction mixture was stirred for 5 min at room temperature and NaBH3CN (609 mg 969 mmol 35 eq) and anhydrous K2CO3 (153 mg 111 mmol 4 eq) were added The reaction was stirred overnight at room temperature and quenched with a saturated solution of NaHCO3 (30 mL) The aqueous phase was extracted 3 times with CH2Cl2

(30 mL) The combined organic phases were dried over anhydrous MgSO4 and filtered off The solvents were removed under reduced pressure and the resulting residue was purified by flash chromatography (n-hexaneEtOAcEt3N 851502) affording (SpSp)-10 with a yield of 756

Rf (n-hexaneEtOAc 73) 0191H-NMR (400 MHz CDCl3) δ = 331 (dd J = 137 Hz J = 68 Hz 1H) 337 (dd J = 137 Hz J = 58 Hz 1H) 372 (d J = 149 Hz 2H) 396 (d J = 149 Hz 2H) 406 (br dd J = 23 Hz J = 13 Hz 2H) 41 (br dd J = 23 Hz J = 21 Hz 2H) 436 (br dd J = 21 Hz J = 13 Hz 2H) 520 (dd J = 103 Hz J = 14 Hz 1H) 521 (dd J = 171 Hz 14 Hz 1H) 596 (dddd J = 171 Hz J = 103 Hz J = 68 Hz J = 58 Hz 1H) ppm13C-NMR (100 MHz CDCl3) δ = 563 (CH2 x2) 594 (CH2) 657 (CH x2) 662 (CH x2) 676 (CH x2) 699 (CH x10) 822 (C x2) 846 (C x2) 1175 (CH2) 1363 (CH) ppm IR (HATR) υmax = 3081 2928 2797 2362 2336 1636 1452 1432 1406 1316 1219 1130 1102 1076 1026 997 975 922 846 810 804 757 cm-1HRMS (ESI) calculated for C25H26Fe2N [M+H]+ 4520759 found 4520751Optical rotation [ α ]D

20=iquest -659deg (c 17 CHCl3)Mp 108-109degC

16 Synthesis of (SpSp)-N-H-35-dihydro-4H-diferrocenyl-[ce]-azepine (SpSp-11)

An oven-dried pressure tube was charged with a magnetic stirring bar (SpSp)-10 (90 mg 020 mmol) and KOt-Bu (112 mg 100 mmol 5 eq) Anhydrous DMSO (70 mL) was added and the pressure tube was closed with a stopper The reaction mixture was heated up to 100degC for 2 h The reaction was allowed to cool to room temperature The dark suspension was diluted with Et 2O (30 mL) and carefully quenched with a saturated solution of NH4Cl (30 mL) The organic phase was separated and washed 3 times with water (30 mL) and once with brine (30 mL) The organic phase was dried over anhydrous MgSO4 and filtered Et2O was removed under reduced pressure and pure (SpSp)-11 was obtained as a yellow solid with a yield of 962

Rf (n-hexaneEtOAcEt3N 271) 0331H-NMR (500 MHz CDCl3) δ = 392 (d J = 160 Hz 2H) 396 (s 10H) 405 (d J = 160 Hz 2H) 411-413 (m 4H) 430 (app t J = 19 Hz 2H) ppm13C-NMR (125 MHz CDCl3) δ = 516 (CH2 x2) 654 (CH x2) 664 (CH x2) 676 (CH x2) 696 (CH x10) 820 (C x2) 880 (C x2) ppmIR (HATR) υmax = 3075 2909 2851 2359 2331 1616 1442 1406 1354 1307 1212 1115 1102 1030 998 809 780 737 674 cm-1HRMS (ESI) calculated for C22H22Fe2N [M+H]+ 4120446 found 4120448Optical rotation [ α ]D

20=iquest -399deg (c 009 CHCl3)Mp 145degC (decomposition)

17 Synthesis of biphenol-based phosphoramidite ligand (6a)

An oven-dried Schlenk tube charged with a magnetic stirring bar and (SpSp)-11 (73 mg 018 mmol) was cooled to 0degC using an ice-water bath A solution of Et3N in toluene (036 M 50 mL 180 mmol 10 eq) was added followed by dropwise addition of a solution of freshly distilled PCl3 in toluene (057 M 316 microL 018 mmol 1 eq) The reaction mixture was stirred for 10 min at 0degC allowed to warm up to room temperature and stirred for an additional 2 h The reaction was cooled again to 0degC and a suspension of 22rsquo-biphenol (33 mg 018 mmol 10 eq) in toluene (30 mL) was added followed by addition of a solution of Et3N in toluene (036 M 12 mL 044 mmol 25 eq) The reaction mixture was stirred for 10 min at 0degC allowed to warm up to room temperature and stirred overnight The reaction was quenched with water (70 mL) and extracted 3 times with CH2Cl2 (70 mL) The combined organic phases were washed with brine (100 mL) dried over anhydrous MgSO4 and filtered The organic solvents were removed under reduced pressure and the resulting residue was purified by flash chromatography (n-hexaneEtOAc 982) affording 6a with a yield of 302 as a yellow solid

Rf (n-hexaneEtOAc 73) 0781H-NMR (400 MHz CDCl3) δ = 390 (dd J = 23 Hz J = 15 Hz 2H) 401 (s 10H) 409 (app t J = 23 Hz 2H) 422 (dd 2JHH = 158 Hz 3JPH = 74 Hz 2H) 436 (dd J = 23 Hz J = 15 Hz 2H) 437 (dd 2JHH = 158 Hz 3JPH = 84 Hz 2H) 687-692 (m 1H) 724-733 (m 4H) 741 (td J = 77 Hz J = 18 Hz 1H) 748-753 (m 2H) ppm13C-NMR (100 MHz CDCl3) δ = 496 (CH2 x2 d JCP = 227 Hz) 656 (CH x2) 662 (CH x2) 678 (CH x2) 698 (CH x10) 819 (C x2) 863 (C x2 d JCP = 44 Hz) 1220 (CH) 1226 (CH) 1243 (CH) 1247 (CH) 1292 (CH) 1293 (CH) 1295 (CH) 1297 (CH) 1305 (C d JCP = 29 Hz) 1312 (C d JCP = 37 Hz) 1510 (C d JCP = 66 Hz) 1512 (C d JCP = 37 Hz) ppm31P-NMR (162 MHz CDCl3) 14457 ppmIR (HATR) υmax = 3083 2953 2922 2854 1474 1433 1365 1245 1225 1189 1123 1097 1042 1031 1005 882 846 818 793 762 732 702 676 cm-1HRMS (ESI) calculated for C34H29Fe2NO2P [M+H]+ 6260629 found 6260617 calculated for C34H28Fe2N2OP [M]+ 6250551 found 6250527Optical rotation [ α ]D


18 Synthesis of (R)-binol-based phosphoramidite ligand (6b)

An oven-dried Schlenk tube charged with a magnetic stirring bar and (SpSp)-11 (30 mg 0073 mmol) was cooled to 0degC using an ice-water bath A solution of Et3N in toluene (036 M 20 mL 073 mmol 10 eq) was added followed by dropwise addition of a solution of freshly distilled PCl3 in toluene (057 M 128 microL 0073 mmol 1 eq) The reaction mixture was stirred for 10 min at 0degC allowed to warm up to room temperature and stirred for an additional 2 h The reaction was cooled again to 0degC and a suspension of (R)-binol (21 mg 0073 mmol 10 eq) in toluene (10 mL) was added followed by addition of a solution of Et3N in toluene (036 M 05 mL 018 mmol 25 eq) The reaction mixture was stirred for 10 min at 0degC allowed to warm up to room temperature and stirred overnight The reaction was quenched with water (25 mL) and extracted 3 times with CH2Cl2 (25 mL) The combined organic phases were washed with brine (40 mL) dried over anhydrous MgSO4 and filtered The organic solvents were removed under reduced pressure and the resulting residue was purified by flash chromatography (n-hexaneEtOAc 982) affording 6b with a yield of 287 as a yellow solid

Rf (n-hexaneEtOAc 73) 0751H-NMR (500 MHz CDCl3) δ = 379 (dd J = 23 Hz J = 15 Hz 2H) 397-401 (m 2H) 398 (s 10H) 400-402 (m 2H) 426 (dd 2JHH = 157 Hz 3JPH = 87 Hz 2H) 429 (dd J = 24 Hz J = 15 Hz 2H) 724-728 (m 1H) 732-737 (m 2H) 739-752 (m 5H) 789-791 (m 2H) 799-803 (m 2H) ppm13C-NMR (125 MHz CDCl3) δ = 496 (CH2 x2 d JCP = 218 Hz) 655 (CH x2) 663 (CH x2) 674 (CH x2) 698 (CH x10) 819 (C x2) 864 (C x2 d JCP = 36 Hz) 1219 (CH) 1221 (CH) 1239 (C d JCP = 55 Hz) 1246 (CH) 1248 (CH) 1261 (CH) 1261 (CH) 1270 (CH x2) 1283 (CH) 1283 (CH) 1301 (CH) 1302 (CH) 1307 (C) 1314 (C) 1327 (C) 1328 (C) 1328 (C) 1496 (C) 1501 (C d JCP = 45 Hz) ppm31P-NMR (162 MHz CDCl3) 14523 ppmIR (HATR) υmax = 3088 2954 2921 2852 1589 1506 1463 1431 1326 1227 1202 1124 1103 1061 1039 1004 951 932 913 820 799 747 697 683 626 cm-1HRMS (ESI) calculated for C42H33Fe2NO2P [M+H]+ 7260942 found 7260922 calculated for C42H32Fe2N2OP [M]+ 7250864 found 7250862Optical rotation [ α ]D


19 Synthesis of (S)-binol-based phosphoramidite ligand (6c)

An oven-dried Schlenk tube charged with a magnetic stirring bar and (SpSp)-11 (60 mg 015 mmol) was cooled to 0degC using an ice-water bath A solution of Et3N in toluene (036 M 41 mL 146 mmol 10 eq) was added followed by dropwise addition of a solution of freshly distilled PCl3 in toluene (057 M 256 microL 015 mmol 1 eq) The reaction mixture was stirred for 10 min at 0degC allowed to warm up to room temperature and stirred for an additional 2 h The reaction was cooled again to 0degC and a suspension of (S)-binol (42 mg 015 mmol 10 eq) in toluene (20 mL) was added followed by addition of a solution of Et3N in toluene (036 M 10 mL 036 mmol 25 eq) The reaction mixture was stirred for 10 min at 0degC allowed to warm up to room temperature and stirred overnight The reaction was quenched with water (50 mL) and extracted 3 times with CH2Cl2 (50 mL) The combined organic phases were washed with brine (80 mL) dried over anhydrous MgSO4 and filtered The organic solvents were removed under reduced pressure and the resulting residue was purified by flash chromatography (n-hexaneEtOAc 982) affording 6c with a yield of 436 as a yellow solid

Rf (n-hexaneEtOAc 73) 0711H-NMR (400 MHz CDCl3) δ = 383 (m 2H) 400 (s 10H) 412 (app t J = 24 Hz 2H) 414 (dd 2JHH = 159 Hz 3JPH = 75 Hz 2H) 435 (dd 2JHH = 160 Hz 3JPH = 83 Hz 2H) 439 (dd J = 24 Hz J = 15 Hz 2H) 705 (d J = 87 Hz 1H) 722-726 (m 1H) 728-736 (m 2H) 740-750 (m 3H) 755 (d J = 88 Hz 1H) 782 (d J = 87 Hz 1H) 790-797 (m 2H) 799 (d J = 88 Hz 1H) ppm13C-NMR (100 MHz CDCl3) δ = 497 (CH2 x2 d JCP = 235 Hz) 655 (CH x2) 661 (CH x2) 682 (CH x2) 699 (CH x10) 820 (C x2) 859 (C x2 JCP = 44 Hz) 1219 (CH) 1229 (CH) 1240 (C JCP

= 51 Hz) 1245 (CH) 1249 (CH) 1259 (CH) 1261 (CH) 1271 (CH x2) 1283 (CH) 1283 (CH) 1302 (CH) 1304 (CH) 1306 (C) 1314 (C) 1325 (C) 1328 (C) 1328 (C) 1491 (C) 1493 (C) 1493 (C) ppm31P-NMR (162 MHz CDCl3) 14347 ppmIR (HATR) υmax = 3089 3054 2958 2923 2853 2359 2341 1619 1590 1506 1462 1431 1366 1328 1261 1229 1204 1124 1104 1043 1066 1031 1007 982 951 927 820 800 750 737 696 cm-1HRMS (ESI) calculated for C42H33Fe2NO2P [M+H]+ 7260942 found 7260899 calculated for C42H32Fe2N2OP [M]+ 7250864 found 7250867Optical rotation [ α ]D


110 Synthesis of Methyl Z-2-acetamido-3-phenylacrylate (12)

An oven-dried 50 mL round-bottom flask was charged with a magnetic stirring bar and α-acetamidocinnamic acid 16 (221 g 107 mmol) Anhydrous DMF (20 mL) anhydrous DIPEA (37 mL 215 mol 2 eq) and iodomethane (27 mL 431 mmol 4 eq) were added The reaction mixture was stirred overnight at room temperature quenched with a saturated solution of NH4Cl (100 mL) and extracted three times with EtOAc (100 mL) The combined organic phases were washed with a 10 mol solution of KHCO3 (100 mL) and a 10 mol solution of citric acid (100 mL) and dried over Na2SO4 After filtration and removal of the organic solvents under reduced pressure the obtained solid was washed with Et2O and n-hexane Methyl Z-2-acetamido-3-phenylacrylate 12 was obtained as a white solid with a yield of 823

Rf (CH2Cl2EtOAc 8515) 0191H-NMR (400 MHz CDCl3) δ = 215 (s 3H) 386 (s 3H) 698 (br s 1H) 710-785 (m 6H) ppm13C-NMR (100 MHz CDCl3) δ = 235 (CH3) 527 (CH3) 1242 (C) 1286 (CH x2) 1295 (CH) 1296 (CH x2) 1322 (CH) 1337 (C) 1657 (C) 1687 (C) ppmESI-MS mz 2421 [M+Na]+ 2201 [M+H]+

111 Rhodium(I)-catalyzed asymmetric hydrogenations of 12 using novel ligands

An oven-dried Schlenk tube was connected to an argon Schlenk line charged with a magnetic stirring bar Rh(COD)2BF4 (28 mg 689 micromol 1 mol) and a ligand (6a 6b or 6c) (138 micromol 2 mol) Degassed2 CH2Cl2 (3 mL) was added to the catalyst mixture which was stirred for 30 min at room temperature Methyl Z-2-acetamido-3-phenylacrylate 12 (151 mg 689 micromol) was added and hydrogen gas was bubbled through the reaction mixture for 10 min The reaction was stirred overnight at room temperature under a hydrogen atmosphere using a balloon The reaction mixture was filtered over a short plug of silica gel and eluted with EtOAc The solvents were removed under reduced pressure and 13 was obtained as a white solid Conversion and enantiomeric excess were determined by chiral LC analysis on a Chiralcel OD-H column (250 x 46 mm particle size 5 microm) solvent n-hexaneEtOH (955) flow rate = 1 mLmin t = 30 min T = 35degC retention times 1120 min for (R)-13 1280 min for (S)-13 and 2081 min for starting material 12 The absolute configuration of 13 was assigned via correlation of its specific rotation with literature values[30]

Rf (CH2Cl2EtOAc 9010) 0181H-NMR (500 MHz CDCl3) δ = 198 (s 3H) 309 (dd J = 139 Hz J = 58 Hz 1H) 314 (dd J = 139 Hz J = 58 Hz 1H) 373 (s 3H) 483 (app dt J = 78 Hz J = 58 Hz 1H) 595 (br s 1H) 707-711 (m 2H) 722-732 (m 3H) ppm13C-NMR (125 MHz CDCl3) δ = 233 (CH3) 380 (CH2) 525 (CH) 532 (CH3) 1273 (CH) 1284 (CH) 1288 (CH) 1359 (C) 1698 (C) 1722 (C) ppmESI-MS mz 2221 [M+H]+ 1801 1621 1201

Chiral HPLC conditionsAgilent1100 series connected to a UV-DAD Chiralcel AS-H column (250 x 46 mm 150 microm particle size) n-hexaneEtOH 955 eluent system 10 ml flow rate 35degC operating temperature and injection of a sample volume of 20 microl of a 1 mgmL sample concentration

Ligand 6a

2Degassing was accomplished by bubbling of H2-gas through the solvent for 10 min using a balloon

(R)-131113 min

(R)-131277 min

Ligand 6b

Ligand 6c

Starting material12 1971 min


(R)-131091 min

(R)-131151 min

(R)-131382 min

(R)-131238 min















Unless otherwise stated all reagents were obtained commercially and used without further purification All reactions were carried out under an argon atmosphere in dry solvents under anhydrous conditions unless otherwise noted Dichloroethane Et3N and DIPEA were dried via distillation over CaH2 Toluene was dried via distillation over sodium with benzophenone as indicator Other anhydrous solvents were purchased as such Analytical TLC was performed by using Machery-Nagel SIL G-25 UV254 plates Flash chromatography was carried out with Rocc silica gel (0040-0063 mm) 1H NMR and 13C NMR spectra were recorded with a Bruker avance 300 or a Bruker Avance 400 or a Bruker AM 500 spectrometer as indicated with chemical shifts reported in ppm relative to TMS by using the residual solvent signal as a standard and relative to 85 aqueous phosphoric acid for 31P NMR spectra IR spectra were recorded with a Perkin-Elmer SPECTRUM-1000 FTIR spectrometer with a Pike Miracle Horizontal Attenuated Total Reflectance (HATR) module ESI-MS was performed on an Agilent 1100 series with a single quadrupole MS detector G1946C (type VL) equipped with an API-ESI source High Resolution Mass Spectrometry (HRMS) was performed on an Agilent 1100 series connected to a 6220A TOF-MS detector equipped with an APCI-ESI multimode source or a Kratos MS50TC mass spectrometer (EI) For all MS-analysis the standard solvent was a 5050 mixture of MeOH5 mM aqueous NH4OAc and a sample volume of 5microL was injected LC-MS analyses were performed on an Agilent 1100 series HPLC connected to a UV-DAD detector and a single quadrupole MS detector G1946C (type VL) equipped with an API-ESI source by using a Phenomenex Kinetex C18 column (150 x 46 mm 5 microm particle size) All measurements were performed at 35degC a flow rate of 1 mLmin and sample volume of 15 microL was injected Mili-Q water and HPLC quality grade CH3CN were used Analytical chiral separations were performed on an Agilent 1100 series HPLC system using a Chiralcel OD-H column (250 x 46 mm 5 microm particle size) or a Chiralpak AS-H column (250 x 46 mm 5 microm particle size) connected to a UV-DAD detector All measurements were performed at 35degC a flow rate of 1 mLmin and a sample volume of 20 microL HPLC quality grade solvents were used for all measurements Optical rotations were measured using a Perkin-Elmer 214 polarimeter at 589 nm



An oven-dried 50 mL round-bottom flask was charged with (Sp)-8 (2610 g 768 mmol) Metallic copper (1950 g 3071 mmol 4 eq) was carefully added in such way that all of the starting material was covered with copper A heavy egg-shaped stirring bar was carefully added and the reaction flask was wrapped in aluminum foil The reaction was stirred overnight at 105degC The crude reaction mixture was taken up in CH2Cl2 and filtered over Celite while the filtrate was collected in a round-bottom flask which was wrapped in aluminum foil The solvent was removed under reduced pressure
















14275 min(SpSp)-9

15889 min(RpRp)-9





6131 min

14719 min(SpSp)-9












































Ligand 6a


(R)-131113 min

(R)-131277 min

Ligand 6b

Ligand 6c



(R)-131091 min

(R)-131151 min

(R)-131382 min

(R)-131238 min





























14275 min(SpSp)-9

15889 min(RpRp)-9





6131 min

14719 min(SpSp)-9












































Ligand 6a


(R)-131113 min

(R)-131277 min

Ligand 6b

Ligand 6c



(R)-131091 min

(R)-131151 min

(R)-131382 min

(R)-131238 min


















6131 min

14719 min(SpSp)-9












































Ligand 6a


(R)-131113 min

(R)-131277 min

Ligand 6b

Ligand 6c



(R)-131091 min

(R)-131151 min

(R)-131382 min

(R)-131238 min

























































Ligand 6a


(R)-131113 min

(R)-131277 min

Ligand 6b

Ligand 6c



(R)-131091 min

(R)-131151 min

(R)-131382 min

(R)-131238 min














Ligand 6b

Ligand 6c



(R)-131091 min

(R)-131151 min

(R)-131382 min

(R)-131238 min














1.1.general experimantal methods · web viewanalytical chiral separations were performed on an...

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