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1 -SUPPRTING INFRMATIN- The Fully Catalytic System in Mitsunobu Reaction Has Not Been Realized Yet Daisuke Hirose,, Martin Gazvoda,, Janez Košmrlj,*, and Tsuyoshi Taniguchi*, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa , Japan Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000, Ljubljana, Slovenia School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa , Japan D.H. and M.G. contributed equally. Table of Contents 1. Experiments by Gazvoda and Košmrlj in Slovenia -Experimental details... S2 -NMR spectra of isolated compounds......s10 2. Experiments by Hirose and Taniguchi in Japan -Experimental details..... S19 -NMR spectra of isolated compounds......s29 3. References S39 S1

2 1. Experiments by Gazvoda and Košmrlj in Slovenia General remarks: All reactions were performed in oven-dried glassware. Molecular sieves were activated by heating with a Bunsen burner in vacuo (ca. 0.9 mbar) for 5 min. Thin-layer chromatography (TLC) analysis was performed by illumination with a UV lamp (254 nm) or by using a solution of KMn 4 /K 2 C 3 /NaH in water (prepared by dissolving 1.5 g of KMn 4, 10 g K 2 C 3 and 1.25 ml 10% NaH in 200 ml of water) followed by heating. Silica gel column chromatography was carried out on silica gel 60N. 1 H NMR spectra were recorded with a Bruker Avance III 500 MHz NMR (500 MHz) instrument at 300 K; chemical shifts (δ) are quoted relative to tetramethylsilane. Determination of enantiomeric ratio was performed by using Daicel-Chiralpak IC 4.6 mm 250 mm, particle size 5 µm and Agilent 1260 Infinity with multi UV-Vis. Tetrahydrofuran was distilled over sodium wire. Pressure vessel: ACE GLASS Inc. (35 ml and 15 ml) xygen, % (Messer xygen 5.0) Starting materials: Benzyl alcohol: Sigma-Aldrich (S)-Ethyl lactate: Sigma-Aldrich 4-Nitrobenzoic acid: Sigma-Aldrich Diisopropyl azodicarboxylate (DIAD): Sigma-Aldrich Iron phthalocyanine [Fe(Pc)]: Sigma-Aldrich Phenylsilane: Sigma-Aldrich Molecular sieves 5 Å (powder): Sigma-Aldrich THF (Tetrahydrofuran inhibitor free for HPLC): Sigma-Aldrich The following materials were prepared according to the literature. 1-Phenylphospholane-1-oxide 1,2 31 P NMR (202 MHz, CDCl 3 ) δ 60.1(s). Literature data: 31 P NMR (121 MHz, CDCl 3 ) δ 59.8 (s) 2 Ethyl 2-(3,4-dichlorophenyl)hydrazinecarboxylate 3 S2

3 Preparation of (S)-1-ethoxycarbonylethyl 4-nitrobenzoate, a standard sample for retention time determination: To a solution of ( )-ethyl lactate (118 mg, 1.0 mmol) and pyridine (158 mg, 2.0 mmol) in dichloromethane (5 ml), 4-nitrobenzoyl chloride (204 mg, 1.1 mmol) was added at 0 C. The reaction mixture was warmed to room temperature at stirred for 16 h. Then, organic phase was diluted with dichloromethane (15 ml) and washed with 1M HCl (10 ml), brine (10 ml), dried over Na 2 S 4, filtered and evaporated under reduced pressure. Flash column chromatography (hexanes/ethyl acetate 6/1) afforded (S)-1-ethoxycarbonylethyl 4-nitrobenzoate as an off-white solid (246 mg, 92%). Me H C 2 Et + Cl N 2 pyridine CH 2 Cl 2, rt 2 N Me C 2 Et 1 H NMR of the product after column chromatography: HPLC analysis to determine er: S3

4 Catalytic Mitsunobu reaction in the azo reagent (Scheme 2, eq 1) The reaction was performed using MS 5 Å (powder) activated by heating with a Bunsen burner in vacuo (ca. 0.9 mbar) for 5 min according to the reported procedure (1.0 mmol scale). 3,4 All spectra were matched against the references. 1,3,4 Me H C 2 Et 2 N (1.0 equiv) (1.1 equiv) C 2 H Cl Cl H N N H C 2 Et (10 mol %) Fe(Pc) (10 mol %) PPh 3 (2.0 equiv) THF (0.5 M) air, MS 5 Å, 65 C, 24 h 2 N Me 1 C 2 Et (R)-1-Ethoxycarbonylethyl 4-nitrobenzoate (1): 233 mg, 87% yield, 99:1 er (R/S). [α] 17.7 (c 0.70, CHCl 3). Literature data: [α] 18.5 (c 1.00, CHCl 3) 4 HPLC analysis to determine er: The enantiomeric ratio was determined by HPLC analysis using a chiral column. Chiral HPLC: Daicel-Chiralpak IC 4.6 mm 250 mm, particle size 5 µm, multi UV-Vis detector (230 nm), room temperature eluent: (n-hexane/i-prh) 85:15, flow rate: 0.5 ml/min, retention time (min) 51 (R isomer), 27 (S isomer). S4

5 Procedure of the catalytic Mitsunobu reaction in the phosphine (Scheme 2, eq 2) 1 To a 15 ml pressure tube equipped with a stir bar phosphine precatalyst (18 mg, 0.10 equiv, 0.10 mmol) and 4-nitrobenzoic acid (251 mg, 1.5 equiv, 1.5 mmol) were added under argon atmosphere. Then, THF (4 ml) was added followed by ( )-ethyl lactate (118 mg, 1.0 mmol), DIAD (222 mg, 1.1 equiv, 1.1 mmol), and phenylsilane (119 mg, 1.1 equiv, 1.1 mmol). The reaction vessel was sealed with a #15 -ring and heated at 80 C for 18 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Column chromatography (hexanes/ethyl acetate 6/1) afforded 1-ethoxycarbonylethyl 4-nitrobenzoate (1). All spectra were matched against the references. 1,3,4 Me C 2 Et C 2 H DIAD (1.1 equiv) 2 N H 2 N (1.0 equiv) (1.5 equiv) P (10 mol %) 1 Ph PhSiH 3 (1.1 equiv) THF (0.25 M) 80 C, 18 h 1st run: 122 mg, 46%, 74:26 er (R/S). Me C 2 Et HPLC analysis to determine er: S5

6 2nd run: 110 mg, 41%, 85:15 er (R/S). HPLC analysis to determine er: General procedure for the fully catalytic Mitsunobu reaction (Figure 1) To a 35 ml pressure tube equipped with a stir bar were added activated powdered molecular sieves 5 Å (500 mg), THF (3 ml), 1-phenylphospholane-1-oxide (9.0 mg, 0.10 equiv, 0.05 mmol, via syringe as standard solution in THF), ethyl 2-(3,4-dichlorophenyl)hydrazinecarboxylate (12.5 mg, 0.10 equiv, 0.05 mmol), Fe(Pc) (28.5 mg, 0.10 equiv, 0.05 mmol), and 4-nitrobenzoic acid (125 mg, 1.5 equiv, 0.75 mmol). Then, alcohol (1.0 equiv, 0.50 mmol), and phenylsilane (59.5 mg, (68 μl), 1.1 equiv, 0.55 mmol) were added to the solution. The vessel was purged with oxygen gas and sealed with a #15 -ring. The reaction mixture was heated at 70 ºC for 48 hours, and then cooled to room temperature, filtered to remove the molecular sieves, and the filtrate was evaporated under reduced pressure. The crude material was analyzed by 1 H NMR and purified by silica gel chromatography (hexanes/etac) to give the corresponding product. All spectra were matched against the references. 1,3,4 S6

7 (1) The reaction between benzyl alcohol and 4-nitrobenzoic acid [entry 1 (2nd run)] Benzyl 4-nitrobenzoate (3): 47 mg, 37% yield. Cl H N N H C 2 Et C 2 H H 2 N (1.0 equiv) (1.5 equiv) 54.1 mg Cl (10 mol %) Fe(Pc) (10 mol %) P Ph (10 mol %) PhSiH 3 (1.1 equiv) THF (0.17 M) 2, MS 5 Å, 70 C, 48 h 3 N 2 The reaction between benzyl alcohol and 4-nitrobenzoic acid [entry 1 (2nd run)] conducted with oxygen generated from NaCl and H The conversion into benzyl 4-nitrobenzoate (3) is 38% as determined by qnmr of the crude product using 1,3,5-trimethoxybenzene as an internal standard. (2) Reaction between ( )-ethyl lactate and 4-nitrobenzoic acid [entry 2 (3rd run)] 1-Ethoxycarbonylethyl 4-nitrobenzoate (1): 8 mg, 6% yield, 16:84 er (R/S). Cl H N N H C 2 Et Me C 2 Et C 2 H Cl (10 mol %) Fe(Pc) (10 mol %) 2 N Me C 2 Et H (1.0 equiv) 59.1 mg 2 N (1.5 equiv) P Ph (10 mol %) PhSiH 3 (1.1 equiv) THF (0.17 M) 2, MS 5 Å, 70 C, 48 h 1 HPLC analysis to determine er: S7

8 (3) The reaction between 3-phenylpropan-1-ol and 4-nitrobenzoic acid using the general procedure [entry 3 (1st and 2nd run)]. A very small amount (<5%) of 3-phenylpropyl 4-nitrobenzoate (4) was detected by 1 H NMR analysis (an internal standard: 1,3,4-trimethoxybenzene). Two unidentified products were also detected. Similarly, a trace amount of 3-phenylpropyl 4- nitrobenzoate (4) was detected in the reaction in the absence of the hydrazine catalyst by 1 H NMR analysis. (4) The reaction between benzyl alcohol and 4-nitrobenzoic acid using only MS 5 Å under argon atmosphere. 1 H NMR analysis of the crude material indicated unreacted starting materials and no formation of 3. (5) The reaction between benzyl alcohol and 4-nitrobenzoic acid using only MS 5 Å and phenylsilane under argon atmosphere. 1 H NMR analysis of the crude material indicated no production of 3, production of two unidentified products and unreacted starting materials. S8

9 (6) The reaction between benzyl alcohol and 4-nitrobenzoic acid using only MS 5 Å and iron phthalocyanine under oxygen atmosphere. 1 H NMR analysis of the crude material indicated trace amounts production of 3, 75% formation of benzaldehyde (by qnmr using 1,3,5- trimethoxybenzene as an internal standard). (7) The reaction between benzyl alcohol and 4-nitrobenzoic acid using MS 5 Å, iron phthalocyanine and phenylsilane under oxygen atmosphere. 1 H NMR analysis of the crude material indicated the absence of ester 3 and production of a small amount of benzaldehyde along with unidentified products. (8) The reaction between benzyl alcohol and 4-nitrobenzoic acid using iron phthalocyanine and tricyclohexylphosphine under oxygen or nitrogen atmosphere. 1 H NMR analysis of the crude material indicated the reaction hardly took place in both cases (Under oxygen atmosphere, a very small amount of benzaldehyde was detected). S9

10 Current Data Parameters NAME MGS-623 EXPN 77 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM spect PRBHD 5 mm PABB BB- PULPRG zg30 TD SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 406 DW usec DE 6.50 usec TE K D sec TD0 1 ======== CHANNEL f1 ======== SF MHz NUC1 1H P usec PLW W F2 - Processing parameters SI SF MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC ppm S10

11 Current Data Parameters NAME MGS-799 EXPN 94 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM spect PRBHD 5 mm PABB BB- PULPRG zg30 TD SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 406 DW usec DE 6.50 usec TE K D sec TD0 1 ======== CHANNEL f1 ======== SF MHz NUC1 1H P usec PLW W F2 - Processing parameters SI SF MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC ppm S11

12 60.11 Current Data Parameters NAME MGS-799 EXPN 42 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM spect PRBHD 5 mm PABB BB- PULPRG zgpg30 TD SLVENT CDCl3 NS 16 DS 4 SWH Hz FIDRES Hz AQ sec RG 2050 DW usec DE 6.50 usec TE K D sec D sec TD0 1 ======== CHANNEL f1 ======== SF MHz NUC1 31P P usec PLW W ======== CHANNEL f2 ======== SF MHz NUC2 1H CPDPRG[2 waltz16 PCPD usec PLW W PLW W PLW W F2 - Processing parameters SI SF MHz WDW EM SSB 0 LB 1.00 Hz GB 0 PC ppm S12

13 Current Data Parameters NAME MGS-811 EXPN 10 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM spect PRBHD 5 mm PABB BB- PULPRG zg30 TD SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 144 DW usec DE 6.50 usec TE K D sec TD0 1 ======== CHANNEL f1 ======== SF MHz NUC1 1H P usec PLW W F2 - Processing parameters SI SF MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC ppm S13

14 Current Data Parameters NAME MGS-807 EXPN 10 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM spect PRBHD 5 mm PABB BB- PULPRG zg30 TD SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 181 DW usec DE 6.50 usec TE K D sec TD0 1 ======== CHANNEL f1 ======== SF MHz NUC1 1H P usec PLW W F2 - Processing parameters SI SF MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC ppm Scheme 2, Eq. 1 87%, 99:1 er (R/S) S14

15 Current Data Parameters NAME MGS-803 EXPN 10 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM spect PRBHD 5 mm PABB BB- PULPRG zg30 TD SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 181 DW usec DE 6.50 usec TE K D sec TD0 1 ======== CHANNEL f1 ======== SF MHz NUC1 1H P usec PLW W F2 - Processing parameters SI SF MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC ppm Scheme 2, Eq. 2, 1st run 46%, 74:26 er (R/S) S15

16 Current Data Parameters NAME MGS-843 EXPN 14 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM spect PRBHD 5 mm PABB BB- PULPRG zg30 TD SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 362 DW usec DE 6.50 usec TE K D sec TD0 1 ======== CHANNEL f1 ======== SF MHz NUC1 1H P usec PLW W F2 - Processing parameters SI SF MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC ppm Scheme 2, Eq. 2, 2nd run 41%, 85:15 er (R/S) S16

17 Current Data Parameters NAME MGS-808 EXPN 5 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM spect PRBHD 5 mm PABB BB- PULPRG zg30 TD SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 144 DW usec DE 6.50 usec TE K D sec TD0 1 ======== CHANNEL f1 ======== SF MHz NUC1 1H P usec PLW W F2 - Processing parameters SI SF MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC ppm Fig. 1, Ent. 1., 2nd run 37% S17

18 Current Data Parameters NAME MGS-809 EXPN 12 PRCN 1 F2 - Acquisition Parameters Date_ Time INSTRUM spect PRBHD 5 mm PABB BB- PULPRG zg30 TD SLVENT CDCl3 NS 16 DS 2 SWH Hz FIDRES Hz AQ sec RG 203 DW usec DE 6.50 usec TE K D sec TD0 1 ======== CHANNEL f1 ======== SF MHz NUC1 1H P usec PLW W F2 - Processing parameters SI SF MHz WDW EM SSB 0 LB 0.30 Hz GB 0 PC ppm Fig. 1, Ent. 2., 3rd run 6%, 16:84 er (R/S) S18

19 2. Experiments by Hirose and Taniguchi in Japan General remarks: All reactions were performed in oven-dried glassware. Molecular sieves were activated by heating with a heat gun (ISHIZAKI ELECTRIC MFG PJ-208A, ca. 450 C) in vacuo (ca. 0.1 mmhg) for 5 min. Thin-layer chromatography (TLC) analysis was performed by illumination with a UV lamp (254 nm) or staining with PMA and heating. Silica gel column chromatography was carried out on silica gel 60N. 1 H NMR spectra were recorded with JEL JNM ECS400 (400 MHz) and JEL JNM ECS500 (500 MHz) spectrometers at K; chemical shifts (δ) are quoted relative to tetramethylsilane. 31 P NMR spectra were recorded with a JEL JNM ECA600 (243 MHz) spectrometer at 298 K, and referenced to external 85% phosphoric acid ( = 0 ppm). The chromatographic separation of enantiomers was performed using a JASC PU-2080 Plus liquid chromatography equipped with Multi UV-Vis (JASC MD-910). Pressure vessel: ACE GLASS Inc. (15 ml) xygen >99.5 %: Uno Sanso Co., Ltd. Starting materials: Benzyl alcohol: Tokyo Chemical Industry Co., Ltd. (TCI) (S)-Ethyl lactate: KANT CHEMICAL C., INC. 4-Nitrobenzoic acid: KANT CHEMICAL C., INC. (R)-1-Phenylethanol: Merck Diisopropyl azodicarboxylate (DIAD): Wako Pure Chemical Industries, Ltd. Iron phthalocyanine [Fe(Pc)]: Tokyo Chemical Industry Co., Ltd. (TCI) Phenylsilane: Tokyo Chemical Industry Co., Ltd. (TCI) Molecular sieves 5 Å (powder): Sigma-Aldrich THF (Tetrahydrofuran, Dehydrated (Stabilizer free) Super plus ): KANT CHEMICAL C., INC. The following materials were prepared according to the literature. 1-Phenylphospholane-1-oxide 1,2 31 P NMR (243 MHz, CDCl 3 ) δ 60.9(s): Literature data: 31 P NMR (121 MHz, CDCl 3 ) δ 59.8 (s) 2 Ethyl 2-(3,4-dichlorophenyl)hydrazinecarboxylate 3 S19

20 Procedure of the catalytic Mitsunobu reaction in the phosphine (Scheme 2, eqs 2 and 3) To a 15 ml pressure tube equipped with a stir bar was added 1-phenylphospholane-1-oxide (18.0 mg, 0.10 equiv, 0.10 mmol), and 4-nitrobenzoic acid (250 mg, 1.5 equiv, 1.5 mmol). The THF (4 ml) was added followed by alcohol (1.0 equiv, 1.0 mmol), DIAD (222 mg (216 µl), 1.1 equiv, 1.1 mmol) and phenylsilane (119 mg (135 µl), 1.1 equiv, 1.1 mmol) were added to the solution. The vessel was purged with N 2 gas and sealed with a #15 -ring. The reaction was heated at 80 ºC for 18 hours. After cooling to room temperature, the reaction mixture was diluted with EtAc and washed with saturated NaHC 3 aq. The organic layer was successively washed with brine, dried with Na 2 S 4 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (n-hexane/etac, 15:1 10:1) to give the corresponding ester. All spectra were matched against the references. 1,3,4 (R)-1-Ethoxycarbonylethyl 4-nitrobenzoate (1): 3rd run: mg, 38% yield, 87:13 er (R/S). The enantiomeric ratio was determined by HPLC analysis using a chiral column. Chiral HPLC: Daicel-Chiralpak AD-H mm, multi UV-Vis detector (250 nm), room temperature eluent: (nhexane/i-prh) 5:1, flow rate: 0.5 ml/min. S20

21 HPLC analysis of a standard sample of (S)-1-ethoxycarbonylethyl 4-nitrobenzoate 4 : HPLC analysis of a standard sample of racemic 1-ethoxycarbonylethyl 4-nitrobenzoate 4 : Retention time (min) 14.2 (R isomer), 17.8 (S isomer). S21

22 HPLC analysis to determine er: Retention time (min) 14.6 (R isomer), 18.2 (S isomer). 4th run (reaction time was 3 hours): 50.1 mg, 19% yield, 87:13 er (R/S). HPLC analysis to determine er: Retention time (min) 14.6 (R isomer), 18.2 (S isomer). S22

(S)-1-phenylethyl 4-nitrobenzoate ((S)-2): 138.1 mg, 51% yield, 77:23 er (S/R). The enantiomeric ratio was determined by HPLC analysis using a chiral column.

23 (S)-1-phenylethyl 4-nitrobenzoate ((S)-2): mg, 51% yield, 77:23 er (S/R). The enantiomeric ratio was determined by HPLC analysis using a chiral column. Chiral HPLC: Daicel-Chiralpak J-H mm, multi UV-Vis detector (270 nm), room temperature eluent: (nhexane/i-prh) 1:1, flow rate: 0.5 ml/min. HPLC analysis of a standard sample of (R)-1-phenylethyl 4-nitrobenzoate 4 : HPLC analysis of a standard sample of racemic 1-phenylethyl 4-nitrobenzoate 4 : S23

24 Retention time (min) 21.2 (R isomer), 25.1 (S isomer). HPLC analysis to determine er: Retention time (min) 21.2 (R isomer), 25.0 (S isomer). S24

25 General procedure for the fully catalytic Mitsunobu reaction (Figure 1) To a 15 ml pressure tube equipped with a stir bar was added 1-phenylphospholane-1-oxide (9.0 mg, 0.10 equiv, 0.05 mmol), ethyl 2-(3,4-dichlorophenyl)hydrazinecarboxylate (12.5 mg, 0.10 equiv, 0.05 mmol), Fe(Pc) (28.5 mg, 0.10 equiv, 0.05 mmol), 4-nitrobenzoic acid (125 mg, 1.5 equiv, 0.75 mmol), and powdered molecular sieves 5 Å (500 mg). After THF (3 ml) was added, alcohol (1.0 equiv, 0.50 mmol) and phenylsilane (59.5 mg, (68 μl), 1.1 equiv, 0.55 mmol) were added to the solution. The vessel was purged with oxygen gas and sealed with a #15 -ring. The reaction was heated at 70 ºC for 48 hours. After cooling to room temperature, the reaction mixture was filtered to remove the molecular sieves, and the filtrate was diluted with EtAc and washed with saturated NaHC 3 aq. The organic layer was successively washed with brine, dried with Na 2 S 4 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (n-hexane/etac, 25:1 10:1) to give the corresponding product. All spectra were matched against the references. 1,3,4 The enantiomeric ratio (for product 1) was determined by HPLC analysis using a chiral column. Chiral HPLC: Daicel-Chiralpak AD-H mm, multi UV-Vis detector (250 nm), room temperature eluent: (n-hexane/i-prh) 5:1, flow rate: 0.5 ml/min. (1) The reaction between benzyl alcohol and 4-nitrobenzoic acid [entry 1 (1st and 3rd runs)] Benzyl 4-nitrobenzoate (3): 1st run: 51.2 mg, 40% yield. 3rd run (without the hydrazine catalyst): 46.3 mg, 36% yield. S25

26 (2) The reaction between ( )-ethyl lactate and 4-nitrobenzoic acid [entry 2 (1st and 2nd runs)] 1-Ethoxycarbonylethyl 4-nitrobenzoate (1): 1st run: 5.0 mg, 4% yield, 12:88 er (R/S). HPLC analysis to determine er: Retention time (min) 15.4 (R isomer), 19.7 (S isomer). S26

05 mmol) instead of 1- phenylphospholane-1-oxide: The crude material was diluted with CDCl 3 and the solution was analyzed by 1 H

27 2nd run: 8.8 mg, 7% yield, 9:91 er (R/S). HPLC analysis to determine er: Retention time (min) 14.8 (R isomer), 18.5 (S isomer). The reaction using 5-phenyldibenzophosphole oxide 1 (13.8 mg, 0.10 equiv, 0.05 mmol) instead of 1- phenylphospholane-1-oxide: The crude material was diluted with CDCl 3 and the solution was analyzed by 1 H NMR with dimethyl sulfone (47.1 mg, 0.50 mmol) as an internal standard (full relaxation was confirmed). The spectrum showed production of a trace amount (<1% yield) of the product. S27

oxide)+phsih 3 ; H 2 (Pc). Two lanes in each sample were used on TLC (n-hexane/etac, 3:1).

28 Photos of TLC of reagents (A) From left to right: Fe(Pc) + cyclic phosphine oxide (1- phenylphospholane-1-oxide); Fe(Pc) + PhSiH 3 ; Fe(Pc) + cyclic phosphine oxide (1-phenylphospholane-1- oxide)+phsih 3 ; H 2 (Pc). Two lanes in each sample were used on TLC (n-hexane/etac, 3:1). (B) From left to right: Fe(Pc) + tri-n-butylphosphine; Fe(Pc) + tri-n-phenylphosphine; Fe(Pc). Two lanes in each sample were used on TLC (n-hexane/etac, 3:1). S28

29 DFILE d1885-1h-1.als CMNT DATIM :53:17 BNUC 1H EXMD single_pulse.ex2 BFRQ MHz BSET 5.30 KHz BFIN 5.47 Hz PINT FREQU Hz SCANS 8 ACQTM sec PD sec PW usec IRNUC 1H CTEMP 19.9 c SLVNT CDCL3 EXREF 0.00 ppm BF 0.12 Hz RGAIN P Ph PPM S29

30 DFILE d p-1.jdf CMNT DATIM :58:52 BNUC 31P EXMD single_pulse_dec BFRQ MHz BSET 4.04 KHz BFIN 1.25 Hz PINT FREQU Hz SCANS 32 ACQTM sec PD sec PW usec IRNUC 1H CTEMP 20.4 c SLVNT CDCL3 EXREF 0.00 ppm BF 1.20 Hz RGAIN 50 P Ph PPM S30

31 DFILE diclhyd-1.jdf CMNT DATIM :37:46 BNUC 1H EXMD single_pulse.ex2 BFRQ MHz BSET 2.41 KHz BFIN 6.01 Hz PINT FREQU Hz SCANS 8 ACQTM sec PD sec PW usec IRNUC 1H CTEMP 19.7 c SLVNT CDCL3 EXREF 0.00 ppm BF 0.12 Hz RGAIN Cl H N NH C 2 Et Cl PPM S31

32 DFILE d als CMNT DATIM :24:43 BNUC 1H EXMD single_pulse.ex2 BFRQ MHz BSET 4.19 KHz BFIN 7.29 Hz PINT FREQU Hz SCANS 32 ACQTM sec PD sec PW usec IRNUC 1H CTEMP 21.3 c SLVNT CDCL3 EXREF 0.00 ppm BF 0.12 Hz RGAIN N Me C 2 Et (R) 2 N Me C 2 Et (S) 38% yield, R/S=87:13 (Scheme 2, Eq. 2, 3rd run) PPM S32

33 DFILE d als CMNT DATIM :08:30 BNUC 1H EXMD single_pulse.ex2 BFRQ MHz BSET 4.19 KHz BFIN 7.29 Hz PINT FREQU Hz SCANS 8 ACQTM sec PD sec PW usec IRNUC 1H CTEMP 22.6 c SLVNT CDCL3 EXREF 0.00 ppm BF 0.12 Hz RGAIN N Me C 2 Et (R) 2 N Me C 2 Et (S) 19% yield, R/S=87:13 (Scheme 2, Eq. 2, 4th run) (reaction time was 3 hours) PPM S33

34 DFILE d als CMNT DATIM :38:54 BNUC 1H EXMD single_pulse.ex2 BFRQ MHz BSET 4.19 KHz BFIN 7.29 Hz PINT FREQU Hz SCANS 8 ACQTM sec PD sec PW usec IRNUC 1H CTEMP 22.6 c SLVNT CDCL3 EXREF 0.00 ppm BF 0.12 Hz RGAIN N Me Ph (S) 2 N Me Ph (R) % yield, S/R=77:23 (Scheme 2, Eq. 3) PPM S34

35 DFILE d1904-purified-1.als CMNT DATIM :41:43 BNUC 1H EXMD single_pulse.ex2 BFRQ MHz BSET 2.41 KHz BFIN 6.01 Hz PINT FREQU Hz SCANS 8 ACQTM sec PD sec PW usec IRNUC 1H CTEMP 20.4 c SLVNT CDCL3 EXREF 0.00 ppm BF 0.12 Hz RGAIN Ph N 2 40% yield, (Figure 1, Entry 1, 1st run) PPM S35

36 DFILE d1933-purified-1.als CMNT DATIM :46:20 BNUC 1H EXMD single_pulse.ex2 BFRQ MHz BSET 4.19 KHz BFIN 7.29 Hz PINT FREQU Hz SCANS 8 ACQTM sec PD sec PW usec IRNUC 1H CTEMP 20.6 c SLVNT CDCL3 EXREF 0.00 ppm BF 0.12 Hz RGAIN Ph N 2 36% yield, (Figure 1, Entry 1, 3rd run) (In the absence of the hydrazine catalyst) PPM S36

37 DFILE d als CMNT DATIM :38:10 BNUC 1H EXMD single_pulse.ex2 BFRQ MHz BSET 2.41 KHz BFIN 6.01 Hz PINT FREQU Hz SCANS 8 ACQTM sec PD sec PW usec IRNUC 1H CTEMP 19.2 c SLVNT CDCL3 EXREF 0.00 ppm BF 0.12 Hz RGAIN N Me C 2 Et (R) 2 N Me C 2 Et (S) 4% yield, R/S=12:88 (Figure 1, Entry 2, 1st run) PPM S37

38 DFILE d als CMNT DATIM :55:31 BNUC 1H EXMD single_pulse.ex2 BFRQ MHz BSET 2.41 KHz BFIN 6.01 Hz PINT FREQU Hz SCANS 8 ACQTM sec PD sec PW usec IRNUC 1H CTEMP 18.8 c SLVNT CDCL3 EXREF 0.00 ppm BF 0.12 Hz RGAIN N Me C 2 Et (R) 2 N Me C 2 Et (S) 7% yield, R/S=9:91 (Figure 1, Entry 2, 2nd run) PPM S38

39 3. References 1) Buonomo, J. A.; Aldrich, C. C. Angew. Chem., Int. Ed. 2015, 54, ) van Kalkeren, H. A.; Leenders, S. H. A. M.; Hommersom, C. R. A.; Rutjes, F. P. J. T.; van Delft, F. L. Chem. Eur. J. 2011, 17, ) Hirose, D.; Taniguchi, T.; Ishibashi, H. Angew. Chem., Int. Ed. 2013, 52, ) Hirose, D.; Gazvoda, M.; Košmrlj, J.; Taniguchi, T. Chem. Sci. 2016, 7, S39

Supporting Information

Supporting Information Wiley-VCH 2006 69451 Weinheim, Germany rganocatalytic Conjugate Addition of Malonates to a,ß-unsaturated Aldehydes: Asymmetric Formal Synthesis of (-)-Paroxetine, Chiral Lactams