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Page 1: Supporting Information - Wiley-VCH fileSupporting Information for Chiral Phosphoric Acid-catalyzed Enantioselective Aza-Friedel-Crafts Reaction of Indoles Masahiro Terada,* Shigeko

Supporting Information

© Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2007

Page 2: Supporting Information - Wiley-VCH fileSupporting Information for Chiral Phosphoric Acid-catalyzed Enantioselective Aza-Friedel-Crafts Reaction of Indoles Masahiro Terada,* Shigeko

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Supporting Information for Chiral Phosphoric Acid-catalyzed Enantioselective Aza-Friedel-Crafts

Reaction of Indoles

Masahiro Terada,* Shigeko Yokoyama, Keiichi Sorimachi, and Daisuke Uraguchi

Graduate School of Science, Department of Chemistry, Tohoku University, Sendai 980-8578, Japan.

General Information: Infrared spectra were recorded on a Shimazu FTIR-8600PC spectrometer. 1H NMR

spectra were recorded on a JEOL GSX-270 (270 MHz) spectrometer. Chemical shifts are reported in ppm from the

solvent resonance as the internal standard (CDCl3: 7.26 ppm). Data are reported as follows: chemical shift,

integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, br = broad, m = multiplet) and

coupling constants (Hz). 13C NMR spectra were recorded on a JEOL GSX-270 (67.8 MHz) spectrometer with

complete proton decoupling. Chemical shifts are reported in ppm from the solvent resonance as the internal

standard (CDCl3: 77.0 ppm). Analytical thin layer chromatography (TLC) was performed on Merck precoated TLC

plates (silica gel 60 GF254, 0.25 mm). Flash column chromatography was performed on silica gel 60N (spherical,

neutral, 100-210 µm; Kanto Chemical Co., Inc.). Optically rotations were measured on a Jasco P-1020 digital

polarimeter with a sodium lamp and reported as follows; [α]Τ ºC D (c = g/100 mL, solvent). Mass spectra analysis

was performed at the Instrumental Analysis Center for Chemistry, Graduate School of Science, Tohoku University.

All reactions were carried out under a nitrogen (N2) atmosphere in dried glassware. All substrate were purified by

column chromatography or distillation prior to use. Dichloromethane, toluene, diethyl ether and tetrahydrofuran

were supplied from Kanto Chemical Co., Inc. as “Dehydrated solvent system”. Other solvents were dried over

activated MS4A and used under N2 atmosphere. The other simple chemicals were purchased and used as such.

N-TBS protected Indoles (2a-2c), N-Boc protected Imines (3a-3n) were prepared by modified literature procedure.

Experimental Section

1. Preparation of N-TBS Protected Indoles.

2. Preparation of N-Boc Protected Aldimines.

3. Screening of Indole Derivatives

4. Aza-Friedel-Crafts Reaction Catalyzed by Chiral Brønsted Acid.

5. X-Ray Crystallographic Analysis of 4aj.

6. DFT Computational Analysis of BINOL-derived Monophosphoric Acid (R)-1.

7. DFT Computational Analysis of Hydrogen-Bonding Pairs (R)-1/3.

Page 3: Supporting Information - Wiley-VCH fileSupporting Information for Chiral Phosphoric Acid-catalyzed Enantioselective Aza-Friedel-Crafts Reaction of Indoles Masahiro Terada,* Shigeko

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1. Preparation of N-TBS Protected Indoles.

NH

1) n-BuLi, THF, 0 °C

2) TBSCl, rt NTBS

Procedure for Preparation of N-TBS Protected Indole (2a: X = H)[1]: To a stirred solution of indole (2.34 g, 20.0

mmol) in tetrahydrofuran (100 mL) was added n-butyllithium (1.58 mol/L in hexane, 13.9 mL, 22 mmol) over 10 min

at 0 ºC. After addition completion, resulting clear solution was added t-butyldimethylsilyl chloride (4.52 g, 30

mmol) and stirring was continued for additional 2 h at room temperature. The resulting solution was diluted with

saturated aqueous NH4Cl and extracted with ethyl acetate. Organic extracts were dried over Na2SO4 and filtered.

After concentration, the residue was purified by distillation (150 ºC, ca. 0.5 mmHg) to give white solid of N-t-

butyldimethylsilyl-indole (2a: X = H, 4.17 g, 90%); 1H NMR (CDCl3, 270 MHz) δ 0.61 (6H, s), 0.93 (9H, s), 6.22

(1H, d, J = 3.0 Hz), 7.08-7.19 (3H, m), 7.52 (1H, d, J = 7.6 Hz), 7.64 (1H, d, J = 7.6 Hz).

NH

Me1) NaH, THF, 0 °C

2) TBSCl, rt NTBS

Me

Procedure for Preparation of N-TBS Protected Indole (2c: X = Me): To a stirred solution of NaH (79 mg, 3.3

mmol) in acetonitrile (3 mL) was added acetonitrile (3 mL) solution of 5-methylindole (394 mg, 3.0 mmol) over 15

min at 0 ºC. After addition completion, resulting clear solution was added t-butyldimethylsilyl chloride (4.52 g, 30

mmol) and stirring was continued for additional 1 h at room temperature. The resulting solution was diluted with

saturated aqueous NH4Cl and extracted with dichloromethane. Organic extracts were dried over Na2SO4 and filtered.

After concentration, the reaction mixture was purified by silica gel column chromatography (Hexane/EtOAc =

20/1-10/1 as eluent) and distillation (150 ºC, ca. 0.5 mmHg) to give yellow oil of 5-Methyl

N-t-butyldimethylsilyl-indole (2c: X = Me, 610 mg, 83%); 1H NMR (CDCl3, 270 MHz) δ 0.64 (6H, s), 0.98 (9H, s),

2.50 (3H, s), 6.59 (1H, d, J = 3.0 Hz), 7.04 (1H, d, J = 8.5 Hz), 7.19 (1H, d, J = 3.0 Hz), 7.46 (1H, t, J = 8.5 Hz), 7.48

(1H, s); 13C NMR (CDCl3, 67.8 MHz) δ -4.1, 19.5, 21.2, 26.3, 104.3, 113.5, 120.3, 122.9, 128.9, 131.0, 131.6, 139.2;

HRMS (ESI) Calcd for C15H23NaNSi ([M+Na]+) 268.1492. Found 268.1492.

NTBS

Br

2b: X = Br[2]: Reaction performed utilizing the same procedure for preparation of 2c: X = Me; yellow oil (89%);

[1] D. Dhanak, C. B. Resse, J. Chem. Soc. Perkin Trans. I 1989, 2181-2186. [2] Y. L. Song, C. Morin, Synlett 2001, 266-268.

Page 4: Supporting Information - Wiley-VCH fileSupporting Information for Chiral Phosphoric Acid-catalyzed Enantioselective Aza-Friedel-Crafts Reaction of Indoles Masahiro Terada,* Shigeko

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1H NMR (CDCl3, 270 MHz) δ 0.620 (3H, s), 0.623 (3H, s), 0.94 (9H, s), 6.58 (1H, d, J = 3.2 Hz), 7.20 (1H, d, J = 3.2

Hz), 7.26 (1H, dd, J = 8.9, 1.8 Hz), 7.40 (1H, d, J = 8.9 Hz), 7.78 (1H, d, J = 1.8 Hz); 13C NMR (CDCl3, 67.8 MHz) δ

-4.1, 19.4, 26.2, 104.3, 113.1, 115.1, 123.1, 124.1, 132.2, 133.2, 139.6; HRMS (ESI) Calcd for C14H20BrNSi

([M+Na]+) 309.0548. Found 309.0549.

2. Preparation of N-Boc Protected Aldimines.[3]

H

NBoc

F

3e: Ar = 2-FC6H4-: 1H NMR (CDCl3, 270 MHz) δ 1.59 (9H, s), 7.14 (1H, t, J = 7.6 Hz), 7.22 (1H, t, J = 7.6 Hz),

7.54 (1H, td, J = 7.6, 1.9 Hz), 8.12 (1H, td, J = 7.6, 1.9 Hz), 9.15 (1H, s); 13C NMR (CDCl3, 67.8 MHz) δ 27.8, 82.4,

116.0 (d, JC-F = 20.6 Hz), 122.0 (d, JC-F = 8.8 Hz), 124.5 (d, JC-F = 3.9 Hz), 128.3, 135.3 (d, JC-F = 9.8 Hz), 162.4,

162.5, 163.8 (d, JC-F = 256.9 Hz); IR (neat): 2982, 1717, 1636, 1229, 1150 cm-1; HRMS (ESI) Calcd for

C12H14FNaNO2 ([M+Na]+) 246.0901. Found 246.0900.

H

NF

Boc

3f: Ar = 3-FC6H4-: 1H NMR (CDCl3, 270 MHz) δ 1.59 (9H, s), 7.25 (1H, tq, J = 8.1, 1.4 Hz), 7.45 (1H, td, J = 8.1,

5.4 Hz), 7.63-7.68 (2H, m), 8.81 (1H, d, J = 1.1 H ); 13C NMR (CDCl3, 67.8 MHz) δ 27.9, 82.6, 115.7 (d, JC-F = 25.5

Hz), 120.4 (d, JC-F = 21.6 Hz), 126.5, 130.4 (d, JC-F = 5.9 Hz), 136.3 (d, JC-F = 6.9 Hz), 162.2, 162.9 (d, JC-F = 248.1

Hz), 167.9; IR (KBr): 2982, 1717, 1641, 1246, 1157 cm-1; HRMS (ESI) Calcd for C12H14FNaNO2 ([M+Na]+)

246.0901. Found 246.0901.

H

NBoc

3m: Ar = 4-i-PrC6H4-: 1H NMR (CDCl3, 270 MHz) δ 1.27 (6H, d, J = 6.8 Hz), 1.59 (9H, s), 2.97 (1H, qui, J = 6.8

Hz), 7.32 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 8.88 (1H, s); 13C NMR (CDCl3, 67.8 MHz) δ 23.5, 27.8, 34.2,

81.7, 126.9, 130.3, 131.7, 155.1, 162.6, 169.7; IR (KBr): 2964, 2870, 1713, 1626, 1269, 1155 cm-1; HRMS (ESI)

Calcd for C15H21NaNO2 ([M+Na]+) 270.1465. Found 270.1465.

H

NBoc

Ph [3] A. G.. Wenzel, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124, 12964-12965.

Page 5: Supporting Information - Wiley-VCH fileSupporting Information for Chiral Phosphoric Acid-catalyzed Enantioselective Aza-Friedel-Crafts Reaction of Indoles Masahiro Terada,* Shigeko

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3m: Ar = 4-PhC6H4-: 1H NMR (CDCl3, 270 MHz) δ 1.61 (9H, s), 7.40-7.50 (3H, m), 7.64 (2H, dt, J = 8.3, 1.6 Hz),

7.70 (2H, dt, J = 8.3, 1.6 Hz), 8.00 (2H, d, J = 8.3 Hz), 8.94 (1H, s); 13C NMR (CDCl3, 67.8 MHz) δ 28.2, 82.3, 127.4,

127.6, 128.5, 129.2, 130.9, 133.2, 139.9, 146.3, 162.8, 169.5; IR (KBr): 2980, 1713, 1622, 1256, 1153 cm-1; This

N-Boc protected imine (3m: Ar = 4-PhC6H4-) was not detected with mass spectra analysis.

3. Screening of Indole Derivatives

As shown in Table I, the Friedel−Crafts reaction of N-unprotected indole (2d) with N-Boc imine (3a) took

place immediately at room temperature without any catalysts (entry 1). To suppress this uncatalyzed pathway in the

F−C reaction, we explored N-protective groups to diminish the reactivity of indoles (2). After several trials,

tert-butyldimethylsilyl group found to be the best. A trace amount of the F−C products was obtained without

catalysts even at room temperature for 24 h (entry 2), whereas monophosphoric acid catalyst (5) significantly

accelerated the reaction of 2a with 3a to provide the corresponding product (4aa) quantitatively (entry 3). In

contrast, the F−C reaction did not proceed even by using catalyst 5 (entry 4), when N-Ts protected indole (2e) was

employed.

NY

+H Ph

NBoc 5

NY

Ph

HNBoc

2a (Y = TBS)

2d (Y = H)

2e (Y = Ts)

3a 4

CDCl3, rt*

O

OP

O

OH

5

Table I. Aza-Friedel-Crafts reaction of Indole derivatives (2) with N-Boc imine (3a) catalyzed by 5.

entry 5 [mol%] 2 time yield (%)

1 - 2d < 5 min 98 a

2 - 2a 24 h < 5 a

3 2 mol% 2a < 10 min 98 b

4 2 mol% 2e 48 h no reaction aNMR yield. bIsolated yield.

4. Aza-Friedel-Crafts Reaction Catalyzed by Chiral Brønsted Acid.

NTBS

+H Ph

NBoc 2 mol% (R)-1b

NTBS

Ph

HNBoc

2a 3a 4aa(CH2Cl)2, -40 °C, 24 h

Page 6: Supporting Information - Wiley-VCH fileSupporting Information for Chiral Phosphoric Acid-catalyzed Enantioselective Aza-Friedel-Crafts Reaction of Indoles Masahiro Terada,* Shigeko

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Representative Procedure for Aza-Friedel-Crafts Reaction of N-TBS protected indole (2) with N-Boc Protected

Aldimines (3): To a dried test tube was weighted the binaphthol monophosphoric acid ((R)-1a: 1.95 mg, 2 mol%,

0.002 mmol) and the atmosphere was replaced with nitrogen. The catalyst was dissolved in

1,1,2,2-tetrachloroethane (1 mL). N-Boc protected imine (3a: Ar = C6H5-, 22.6 mg, 1.1 equiv, 0.11 mmol) and

N-TBS protected indole (2a: X = H, 23.1 mg, 0.10 mmol) were introduced at -40 °C in this order. The resulting

solution was stirred for 24 hours under the condition, then the reaction was quenched by addition of saturated

aqueous NaHCO3 (1 drop). The reaction mixture was poured on silica gel column and purified by column

chromatography (hexane/EtOAc = 12/1-8/1 as eluent). F-C product (4aa) was obtained in 85% yield as white solid.

Enantiomeric excess was determined by HPLC analysis. 4aa: Rf = 0.62 (Hexane/EtOAc = 2/1); HPLC analysis

Chiralpak AD-H (Hexane/iPrOH = 98/2, 1.0 mL/min, 254 nm, 10 °C) 9.1, 11.9 (major) min, (96% ee); [α]22D = -42.9

(c 1.11, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 0.54 (3H, s), 0.55 (3H, s), 0.91 (9H, s), 1.47 (9H, s), 5.22 (1H, brs),

6.21 (1H, brd, J = 6.2 Hz), 6.78 (1H, s), 7.08 (1H, td, J = 7.8, 1.2 Hz), 7.17 (1H, dt, J = 7.8, 1.2 Hz), 7.25-7.51 (7H,

m); 13C NMR (CDCl3, 67.8 MHz) δ -4.0, 19.4, 26.2, 28.4, 51.7, 79.5, 114.1, 119.4, 119.5, 119.8, 121.8, 126.8, 127.0,

128.3, 129.2, 129.7, 141.9, 141.9, 155.2; IR (KBr): 3454, 2957, 2858, 1701, 1491, 1258, 1163, 1146 cm-1; HRMS

(ESI) Calcd for C26H36NaN2O2Si ([M+Na]+) 459.2438. Found 459.2438.

NTBS

HNBocBr

4ba: Rf = 0.64 (Hexane/EtOAc = 4/1); HPLC analysis Chiralpak AD-H (Hexane/iPrOH = 98/2, 0.7 mL/min, 254 nm,

10 °C) 11.7, 20.6 (major) min (94% ee); [α]22D = -25.1 (c 1.07, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 0.521 (3H, s),

0.524 (3H, s), 0.87 (9H, s), 1.47 (9H, s), 5.16 (1H, brs), 6.13 (1H, d, J = 7.0 Hz ), 6.76 (1H, s), 7.22 (1H, dd, J = 8.6,

1.8 Hz), 7.28-7.36 (6H, m), 7.56 (1H, d, J = 1.8 Hz); 13C NMR (CDCl3, 67.8 MHz) δ -4.1, 19.4, 26.2, 28.4, 51.5, 79.8,

113.2, 115.4, 119.3, 122.0, 124.7, 126.8, 127.3, 128.4, 130.9, 131.1, 140.6, 141.4, 155.2; IR (KBr): 3418, 2959, 2858,

1701, 1495, 1448, 1258, 1157 cm-1; HRMS (ESI) Calcd for C26H35BrNaN2O2Si ([M+Na]+) 537.1543, 539.1523.

Found 537.1545, 537.1522.

NTBS

HNBocMe

4ca: Rf = 0.61 (Hexane/EtOAc = 4/1); HPLC analysis Chiralpak AD-H (Hexane/iPrOH = 98/2, 1.0 mL/min, 254 nm,

10 °C) 10.0, 22.7 (major) min (91% ee); [α]22D = -34.8 (c 1.19, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 0.51 (3H, s),

0.52 (3H, s), 0.89 (9H, s), 1.47 (9H, s), 2.41 (3H, s), 5.21 (1H, brs), 6.19 (1H, d, J = 7.0 Hz), 6.69 (1H, s), 7.00 (1H,

dd, J = 8.5, 1.6 Hz), 7.24-7.42 (7H, m); 13C NMR (CDCl3, 67.8 MHz) δ -4.1, 19.4, 21.3, 26.2, 28.4, 51.6, 79.4, 113.7,

119.1, 123.4, 126.8, 126.9, 128.2, 129.0, 129.5, 129.8, 129.9, 140.1, 142.0, 155.2; IR (KBr): 3458, 2959, 2858,

1701, 1495, 1261, 1138 cm-1; HRMS (ESI) Calcd for C27H38NaN2O2Si ([M+Na]+) 473.2595. Found 473.2595.

Page 7: Supporting Information - Wiley-VCH fileSupporting Information for Chiral Phosphoric Acid-catalyzed Enantioselective Aza-Friedel-Crafts Reaction of Indoles Masahiro Terada,* Shigeko

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NTBS

HNBoc

Me

4ab: Rf = 0.64 (Hexane/EtOAc = 2/1); HPLC analysis Chiralpak AD-H (Hexane/iPrOH = 98/2, 1.0 mL/min, 254 nm,

10 °C) 7.1, 12.5 (major) min (91% ee); [α]21D = -34.2 (c 0.98, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 0.49 (3H, s),

0.51 (3H, s), 0.86 (9H, s), 1.47 (9H, s), 2.29 (3H, s), 5.17 (1H, d, J = 7.6 Hz), 6.34 (1H, d, J = 7.6 Hz), 6.53 (1H, s),

7.08-7.25 (5H, m), 7.39 (1H, d, J = 7.4 Hz), 7.48 (1H, d, J = 7.4 Hz), 7.56 (1H, d, J = 7.4 Hz); 13C NMR (CDCl3,

67.8 MHz) δ -4.0, 19.1, 19.3, 26.2, 28.4, 48.7, 79.4, 114.0, 119.0, 119.4, 119.8, 121.8, 125.6, 125.9, 127.0, 129.6,

129.9, 130.4, 135.7, 140.0, 141.9, 155.1; IR (KBr): 3466, 2958, 2858, 1701, 1489, 1452, 1261, 1144 cm-1; HRMS

(ESI) Calcd for C27H38NaN2O2Si ([M+Na]+) 473.2595. Found 473.2596.

NTBS

HNBoc

Me

4ac: Rf = 0.61 (Hexane/EtOAc = 2/1); HPLC analysis Chiralpak AD-H (Hexane/iPrOH = 98/2, 0.7 mL/min, 254 nm,

10 °C) 12.6, 14.4 (major) min (94% ee); [α]22D = -19.7 (c 0.86, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 0.58 (6H, s),

0.96 (9H, s), 1.50 (9H, s), 2.37 (3H, s) 5.22 (1H, brs), 6.18 (1H, brs), 6.82 (1H, s), 7.10-7.29 (6H, m), 7.49-7.53 (2H,

m); 13C NMR (CDCl3, 67.8 MHz) δ -4.0, 19.4, 21.5, 26.2, 28.4, 51.6, 79.5, 114.0, 119.5, 119.66, 119.74, 121.7, 123.8,

127.6, 127.8, 128.2, 129.3, 129.7, 137.8, 141.9, 141.9, 155.2; IR (KBr): 3450, 2959, 2858, 1701, 1491, 1258, 1163

cm-1; HRMS (ESI) Calcd for C27H38NaN2O2Si ([M+Na]+) 473.2595. Found 473.2595.

NTBS

HNBoc

Me

4ad: Rf = 0.67 (Hexane/EtOAc = 2/1); HPLC analysis Chiralpak AD-H (Hexane/iPrOH = 98/2, 1.0 mL/min, 254 nm,

10 °C) 8.9, 11.5 (major) min (96% ee); [α]21D = -23.8 (c 1.03, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 0.55 (3H, s),

0.56 (3H, s), 0.91 (9H, s), 1.46 (9H, brs), 2.35 (3H, s), 5.19 (1H, brs), 6.17 (1H, brs), 6.81 (1H, s), 7.07 (1H, td, J =

8.0, 1.0 Hz ), 7.13-7.19 (3H, m), 7.28 (2H, d, J = 8.2 Hz), 7.45 (1H, dd, J = 8.0, 1.0 Hz), 7.49 (1H, d, J = 8.0 Hz); 13C

NMR (CDCl3, 67.8 MHz) δ -4.0, 19.4, 21.1, 26.3, 28.4, 51.5, 79.4, 114.0, 119.5, 119.66, 119.71, 121.7, 126.7, 129.0,

129.3, 129.6, 136.5, 139.0, 141.9, 155.2; IR (KBr): 3422, 2955, 2858, 1701, 1491, 1258, 1163 cm-1; HRMS (ESI)

Calcd for C27H38NaN2O2Si ([M+Na]+) 473.2595. Found 473.2596.

NTBS

HNBoc

F

4ae: Rf = 0.58 (Hexane/EtOAc = 2/1); HPLC analysis Chiralpak AD-H (Hexane/iPrOH = 98/2, 1.0 mL/min, 254 nm,

10 °C) 10.4, 15.2 (major) min (83% ee); [α]23D = -42.0 (c 1.23, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 0.52 (3H, s),

0.54 (3H, s), 0.89 (9H, s), 1.46 (9H, s), 5.32 (1H, brs), 6.40 (1H, brs), 6.73 (1H, s), 7.02-7.32 (5H, m), 7.44-7.50 (2H,

Page 8: Supporting Information - Wiley-VCH fileSupporting Information for Chiral Phosphoric Acid-catalyzed Enantioselective Aza-Friedel-Crafts Reaction of Indoles Masahiro Terada,* Shigeko

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m), 7.59 (1H, d, J = 7.2 Hz); 13C NMR (CDCl3, 67.8 MHz) δ -4.0, 19.4, 26.2, 28.3, 47.3, 79.6, 114.1, 115.6 (d, JC-F =

21.2 Hz), 118.2, 119.2, 119.8, 121.8, 124.0 (d, JC-F = 3.4 Hz), 128.35, 128.32, 128.8 (d, JC-F = 7.9 Hz), 129.2 (d, JC-F =

10.8 Hz), 129.3, 141.8, 155.0, 160.6 (d, JC-F = 247.1 Hz); IR (KBr): 3449, 2959, 2856, 1701, 1491, 1256, 1148 cm-1;

HRMS (ESI) Calcd for C26H35FNaN2O2Si ([M+Na]+) 477.2344. Found 477.2345.

NTBS

HNBoc

F

4af: Rf = 0.65 (Hexane/EtOAc = 2/1); HPLC analysis Chiralpak AD-H (Hexane/iPrOH = 98/2, 0.7 mL/min, 254 nm,

10 °C) 12.9, 15.8 (major) min (89% ee); [α]22D = -45.4 (c 1.17, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 0.550 (3H, s),

0.552 (3H, s), 0.91 (9H, s), 1.47 (9H, s), 5.21 (1H, brs), 6.19 (1H, brs), 6.79 (1H, s), 6.96 (1H, td, J = 8.0, 2.0 Hz),

7.06-7.21 (4H, m), 7.30 (1H, td, J = 8.1, 5.9 Hz), 7.45 (1H, d, J = 7.2 Hz), 7.50 (1H, d, J = 7.2 Hz); 13C NMR (CDCl3,

67.8 MHz) δ -4.0, 19.4, 26.2, 28.4, 51.3, 79.7, 113.7 (d, JC-F = 22.1 Hz), 113.9 (d, JC-F = 21.2 Hz), 114.2, 118.8, 119.2,

119.9, 122.0, 122.4 (d, JC-F = 3.0 Hz), 129.0, 129.75 (d, JC-F = 7.9 Hz), 129.76, 141.9, 144.8, 155.2, 162.9 (d, JC-F =

245.0 Hz); IR (KBr): 3454, 2966, 2854, 1703, 1489, 1261, 1173, 1144 cm-1; HRMS (ESI) Calcd for

C26H35FNaN2O2Si ([M+Na]+) 477.2344. Found 477.2345.

NTBS

HNBoc

F

4ag: Rf = 0.63 (Hexane/EtOAc = 2/1); HPLC analysis Chiralpak AD-H (Hexane/iPrOH = 98/2, 0.7 mL/min, 254 nm,

10 °C) 14.0, 15.6 (major) min (97% ee); [α]22D = -40.8 (c 1.24, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 0.547 (3H, s),

0.551 (3H, s), 0.91 (9H, s), 1.46 (9H, s), 5.20 (1H, brs), 6.17 (1H, brs), 6.76 (1H, s), 7.03 (2H, dd, J = 8.5, 2.5 Hz),

7.10 (1H, td, J = 8.0, 1.2 Hz), 7.18 (1H, td, J = 8.0, 1.2 Hz), 7.35 (1H, dt, J = 8.5, 2.5 Hz), 7.37 (1H, dt, J = 8.5, 2.5

Hz), 7.43 (1H, d, J = 8.0 Hz), 7.50 (1H, d, J = 8.0 Hz); 13C NMR (CDCl3, 67.8 MHz) δ -3.9, 19.6, 26.4, 28.5, 51.3,

79.8, 114.1, 115.1 (d, JC-F = 3.0 Hz), 119.3, 119.3, 120.0, 121.9, 128.3 (d, JC-F = 8.3 Hz), 129.0, 129.7, 137.8, 141.9,

155.2, 161.9 (d, JC-F = 244.1 Hz); IR (KBr): 3449, 2957, 2858, 1701, 1508, 1258, 1163, 1146 cm-1; HRMS (ESI)

Calcd for C26H35FNaN2O2Si ([M+Na]+) 477.2344. Found 477.2345.

NTBS

HNBoc

Cl

4ah: Rf = 0.57 (Hexane/EtOAc = 2/1); HPLC analysis Chiralcel OD-H (Hexane/10%iPrOH = 98/2, 1.0 mL/min, 254

nm, 10 °C) 14.6, 17.7 (major) min (87% ee); [α]20D = -38.6 (c 1.15, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 0.55 (6H,

s), 0.90 (9H, s), 1.46 (9H, brs), 5.19 (1H, brs), 6.16 (1H, brs), 6.78 (1H, s), 7.09 (1H, t, J = 7.3 Hz), 7.18 (1H, t, J =

7.3 Hz ), 7.26 (3H, s), 7.40 (1H, s), 7.45 (1H, d, J = 8.0 Hz), 7.50 (1H, d, J = 8.0 Hz); 13C NMR (CDCl3, 67.8 MHz) δ

-4.0, 19.4, 26.2, 28.4, 51.3, 79.8, 114.2, 118.8, 119.2, 120.0, 122.0, 125.0, 126.9, 127.2, 129.0, 129.6, 129.8, 134.2,

141.9, 144.2, 155.2; IR (KBr): 3449, 2962, 2856, 1717, 1491, 1258, 1163 cm-1; HRMS (ESI) Calcd for

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C26H35ClNaN2O2Si ([M+Na]+) 493.2049. Found 493.2050.

NTBS

HNBoc

Cl

4ai: Rf = 0.68 (Hexane/EtOAc = 2/1); HPLC analysis Chiralcel OD-H (Hexane/iPrOH = 98/2, 0.7 mL/min, 254 nm,

10 °C) 7.8, 9.1 (major) min (98% ee); [α]21D = -14.1 (c 1.05, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 0.54 (6H, s),

0.90 (9H, s), 1.45 (9H, s), 5.17 (1H, brs), 6.14 (1H, brs), 6.75 (1H, s), 7.09 (1H, td, J = 7.8, 1.2 Hz), 7.18 (1H, td, J =

7.8, 1.2 Hz), 7.28-7.36 (4H, m), 7.43 (1H, d, J = 7.8 Hz), 7.49 (1H, d, J = 7.8 Hz); 13C NMR (CDCl3, 67.8 MHz) δ

-4.0, 19.4, 26.2, 28.4, 51.2, 79.7, 114.2, 118.9, 119.2, 119.9, 122.0, 128.2, 128.5, 129.0, 129.7, 132.7, 140.6, 141.9,

155.2; IR (KBr): 3422, 2957, 2858, 1686, 1491, 1258, 1163 cm-1; HRMS (ESI) Calcd for C26H35ClNaN2O2Si

([M+Na]+) 493.2049. Found 493.2049.

NTBS

HNBoc

Br

4aj: Rf = 0.65 (Hexane/EtOAc = 2/1); HPLC analysis Chiralcel OD-H (Hexane/iPrOH = 98/2, 0.2 mL/min, 254 nm,

10 °C) 27.4, 31.3 (major) min (98% ee); [α]22D = -34.8 (c 1.19, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 0.54 (6H, s),

0.89 (9H, s), 1.45 (9H, brs), 5.19 (1H, brs), 6.13 (1H, brd, J = 7.6 Hz), 6.75 (1H, s), 7.08 (1H, td, J = 8.0, 1.2 Hz),

7.17 (1H, td, J = 8.0, 1.2 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.41-7.50 (4H, m); 13C NMR (CDCl3, 67.8 MHz) δ -4.0, 19.4,

26.2, 28.4, 51.3, 79.8, 114.2, 118.9, 119.3, 120.0, 120.8, 122.0, 128.5, 129.0, 129.7, 131.4, 141.2, 141.9, 155.2; IR

(KBr): 3435, 2930, 2858, 1701, 1489, 1452, 1258, 1146 cm-1; HRMS (ESI) Calcd for C26H35BrNaN2O2Si ([M+Na]+)

537.1543, 539.1523. Found 537.1544, 539.1524.

NTBS

HNBoc

CF3

4ak: Rf = 0.70 (Hexane/EtOAc = 2/1); HPLC analysis Chiralcel OD-H (Hexane/10%iPrOH = 98/2, 1.0 mL/min, 254

nm, 10 °C) 18.9, 21.8 (major) min (93% ee); [α]22D = -25.1 (c 1.01, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 0.54 (3H,

s), 0.55 (3H, s), 0.90 (9H, s), 1.46 (9H, s), 5.23 (1H, brs), 6.22 (1H, brs), 6.76 (1H, s), 7.10 (1H, td, J = 7.8, 1.2 Hz),

7.19 (1H, td, J = 7.8, 1.2 Hz), 7.45 (1H, d, J = 7.8 Hz), 7.50 (1H, d, J = 7.8 Hz), 7.52 (2H, d, J = 8.0 Hz), 7.61 (2H, d,

J = 8.0 Hz); 13C NMR (CDCl3, 67.8 MHz) δ -4.0, 19.4, 26.2, 28.3, 51.5, 79.9, 114.3, 118.5, 119.1, 120.0, 122.1,

124.3 (q, JC-F = 271.2 Hz), 125.3 (q, JC-F = 3.9 Hz), 127.0 128.9, 129.2 (q, JC-F = 32.4 Hz), 129.8, 141.9, 146.2, 155.2;

IR (KBr): 3450, 2957, 2858, 1701, 1327, 1259, 1165 cm-1; HRMS (ESI) Calcd for C27H35F3NaN2O2Si ([M+Na]+)

527.2312. Found 527.2312.

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NTBS

HNBoc

OMe

4al: Rf = 0.58 (Hexane/EtOAc = 2/1); HPLC analysis Chiralpak AD-H (Hexane/iPrOH = 98/2, 1.0 mL/min, 254 nm,

10 °C) 15.7, 23.2 (major) min (89% ee); [α]22D = -12.4 (c 1.03, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 0.54 (3H, s),

0.55 (3H, s), 0.90 (9H, s), 1.46 (9H, brs), 3.81 (3H, s), 5.16 (1H, brs), 6.13 (1H, brs), 6.80 (1H, s), 6.87 (2H, dt, J =

8.7, 2.4 Hz), 7.06 (1H, t, J = 8.0 Hz), 7.16 (1H, td, J = 8.0, 1.0 Hz), 7.30 (2H, d, J = 8.7 Hz), 7.43 (1H, d, J = 8.0 Hz),

7.48 (1H, d, J = 8.0 Hz); 13C NMR (CDCl3, 67.8 MHz) δ -4.0, 19.4, 26.3, 28.4, 51.2, 55.2, 79.4, 113.7, 114.1, 119.5,

119.72, 119.75, 121.8, 128.0, 129.3, 129.6, 134.2, 141.9, 155.2, 158.6; IR (KBr): 3423, 2957, 2858, 1718, 1508, 1258,

1167 cm-1; HRMS (ESI) Calcd for C27H38NaN2O3Si ([M+Na]+) 489.2544. Found 489.2545.

NTBS

HNBoc

iPr

4am: Rf = 0.67 (Hexane/EtOAc = 2/1); HPLC analysis Chiralpak AD-H (Hexane/iPrOH = 98/2, 1.0 mL/min, 254 nm,

10 °C) 9.4, 21.5 (major) min (97% ee); [α]22D = -15.6 (c 0.97, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 0.545 (3H, s),

0.550 (3H, s), 0.91 (9H, s), 1.25 (6H, d, J = 7.0 Hz), 1.46 (9H, brs), 2.90 (1H, qui, J = 7.0 Hz), 5.21 (1H, s), 6.17 (1H,

d, J = 7.5 Hz), 6.83 (1H, s), 7.06 (1H, td, J = 8.0, 1.2 Hz), 7.16 (1H, td, J = 8.0, 1.2 Hz), 7.18 (2H, d, J = 8.0 Hz),

7.29 (2H, d, J = 8.0 Hz), 7.44 (1H, d, J = 8.0 Hz), 7.48 (1H, d, J = 8.0 Hz); 13C NMR (CDCl3, 67.8 MHz) δ -4.1, 19.4,

21.26, 21.29, 26.2, 28.4, 51.6, 79.4, 113.7, 119.1, 123.4, 126.8, 126.9, 128.2, 129.0, 129.5, 129.8, 129.9, 140.1, 142.0,

155.2; IR (KBr): 3447, 2959, 2860, 1701, 1491, 1258, 1165 cm-1; HRMS (ESI) Calcd for C29H42NaN2O2Si

([M+Na]+) 501.2908. Found 501.2909.

NTBS

HNBoc

Ph

4an: Rf = 0.68 (Hexane/EtOAc = 2/1); HPLC analysis Chiralpak AD-H (Hexane/iPrOH = 98/2, 1.0 mL/min, 254 nm,

10 °C) 16.1, 24.5 (major) min (97% ee); [α]21D = -10.5 (c 0.98, CHCl3); 1H NMR (CDCl3, 270 MHz) δ 0.55 (3H, s),

0.56 (3H, s), 0.91 (9H, s), 1.48 (9H, bs), 5.24 (1H, bs), 6.23 (1H, bs), 6.84 (1H, s), 7.09 (1H, td, J = 7.6, 1.4 Hz), 7.18

(1H, td, J = 7.6, 1.4 Hz), 7.34 (1H, tt, J = 7.6, 1.4 Hz), 7.41-7.52 (6H, m), 7.57-7.67 (4H, m); 13C NMR (CDCl3, 67.8

MHz) δ -4.0, 19.4, 26.3, 28.4, 51.5, 79.6, 114.1, 119.39, 119.45, 119.8, 121.9, 127.0, 127.1, 127.2, 128.7, 129.2,

129.70, 129.74, 130.3, 139.8, 140.9, 141.9, 155.3; IR (KBr): 3412, 2957, 2856, 1701, 1487, 1258, 1169 cm-1; HRMS

(ESI) Calcd for C32H40NaN2O2Si ([M+Na]+) 535.2751. Found 535.2751.

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5. X-Ray Crystallographic Analysis of 4aj.

Figure I. ORTEP diagram of (S)-4aj. The absolute configuration was defined to be S by refinement of the flack

parameter. Full listings of the atomic coordinates, bond lengths and angles have been deposited with Cambridge

Crystallographic Data as supplementary publication no CCDC 637961.

EXPERIMENTAL DETAILS

A. Crystal Data Empirical Formula C26H35N2O2BrSi Formula Weight 515.56 Crystal Color, Habit colorless, prism Crystal Dimensions 0.20 X 0.20 X 0.20 mm Crystal System orthorhombic Lattice Type Primitive Detector Position 49.80 mm Pixel Size 0.137 mm Lattice Parameters a = 10.604(2) Å b = 12.231(3) Å

Br N

N

SitBu Me

Me

O

OtBu

H

(S)-4aj

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c = 20.967(5) Å V = 2719.3(11) Å3 Space Group P212121 (#19) Z value 4 Dcalc 1.259 g/cm3 F000 1080.00 µ(MoKα) 15.83 cm-1

B. Intensity Measurements Detector Rigaku Mercury Goniometer Rigaku AFC8 Radiation MoKα (λ = 0.71070 Å) graphite monochromated Detector Aperture 70 mm x 70 mm Data Images 1800 exposures ω oscillation Range (χ=45.0, φ=0.0) -70.0 - 110.0o Exposure Rate 75.0 sec./o Detector Swing Angle 20.08o ω oscillation Range (χ=45.0, φ=90.0) -70.0 - 110.0o Exposure Rate 75.0 sec./o Detector Swing Angle 20.08o ω oscillation Range (χ=45.0, φ=180.0) -70.0 - 110.0o Exposure Rate 75.0 sec./o Detector Swing Angle 20.08o ω oscillation Range (χ=45.0, φ=270.0) -70.0 - 110.0o Exposure Rate 75.0 sec./o Detector Swing Angle 20.08o Detector Position 49.80 mm Pixel Size 0.137 mm 2θmax 55.0o

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No. of Reflections Measured Total: 38174 Unique: 6209 (Rint = 0.036) Corrections Lorentz-polarization Absorption (trans. factors: 0.9230 - 1.0000)

C. Structure Solution and Refinement

Structure Solution Direct Methods (SIR92) Refinement Full-matrix least-squares on F Function Minimized Σ w (|Fo| - |Fc|)2 Least Squares Weights 1/σ2(Fo) 2θmax cutoff 53.0o Anomalous Dispersion All non-hydrogen atoms No. Observations (I>3.00σ(I)) 2491 No. Variables 290 Reflection/Parameter Ratio 8.59 Residuals: R (I>3.00σ(I)) 0.067 Residuals: Rw (I>3.00σ(I)) 0.077 Goodness of Fit Indicator 2.099 Flack Parameter (Friedel Pairs = 2694) 0.02(3) Max Shift/Error in Final Cycle 0.000 Maximum peak in Final Diff. Map 1.38 e-/Å3 Minimum peak in Final Diff. Map -1.17 e-/Å3

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6. DFT Computational Analysis of BINOL-derived Monophosphoric Acid (R)-1.

Computational Details.

Geometries of all stationary points were optimized using analytical energy gradients of

self-consistent-field[ 4 ] and density functional theory (DFT)[ 5 ]. The latter utilized Beck’s three-parameter

exchange-correction functional[6] including the nonlocal gradient corrections described by Lee-Yang-Parr (LYP),[7] as

implemented in the Gaussian 03 program package.[8] Geometry optimizations of all conformers were performed

using the B3LYP/6-31G(d,p) basis set.

7. DFT Computational Analysis of Hydrogen-Bonding Pairs (R)-1/3.

In an effort to investigate the high enantioselectivity in the present F−C reaction and the inversion in the

stereochemical outcome observed in the catalysis between (R)-1a and (R)-1b, we conducted computational

analysis[6d] of the hydrogen-bonding pairs of the catalysts (1) with N-Boc imine (3a) at the B3LYP/6-31G** level of

theory. The optimized 3D-structures of the associates (R)-1b/3a and (R)-1a/3a are shown in Figures II and III,

respectively. The result show that the key feature of the stereochemical control by 1 is high flexibility within the

hydrogen bonding, which allows the imine C=N bond to adopt the most accessible orientation.

7.1. Computational Analysis of Hydrogen-Bonding Pairs, (R)-1b/3a Complexes:

Inspection of Table II and Figure II reveals that associate A was optimized as the lowest energy conformer,

however, both enantiotopic faces of the imine C=N bond are well shielded by the two TPH substituents. In contrast,

B is relatively unfavorable as compared with A but the nucleophiles (indoles) is fully accessible to one enantiotopic

face (re-face) of the imine C=N bond (blue arrow indicated in B). The other face (si-face) of the imine is effectively

shielded by one of the TPH substituents, where π-π interactions would lead to parallel orientation between the TPH

and the activated imine, thus the electron deficient C=N bond. Based on these computational analyses, and

assuming that the enantioselective reaction proceeds through the associate B, the re-face of imine should be attacked

by the nucleophiles to afford (S)-product; this would explain the enantioselectivity observed in the (R)-1b-catalyzed

reaction of 2 with 3. In addition, the reduction in catalytic efficiency with ortho substitution as shown in Table 2

(entries 3 and 7) is presumably due to a reduction in π-π interactions. Deviation from coplanarity between the

[4] P. Pulay in Modern Theoretical Chemistry, Vol. 4 (Ed.: H. F. Schaefer), Plenum, New York, 1977, pp. 153. [5] R. G. Parr, W. Yang, Density Functional Theory of Atoms and Molecules, Oxford University Press, New York,

1989. [6] A. D. Becke, J. Chem. Phys. 1993, 98, 5648. [7] C. Lee, W. Yang, R. G. Parr, Phys. Rev. B, 1993, 37, 785. [8] Gaussian 03, Revision D.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.

Cheeseman, J. A. Montgomery, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc., Wallingford CT, 2004.

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aromatic ring and the imine C=N bond owing to introduction of the ortho substituent might disturb the parallel

arrangement of the TPH substituent. Several hydrogen-bonding pairs of 1b/3 with local minima were obtained from

the DFT calculation. However, in most cases these conformers closely resembled associates A or B. The other

geometrically distinct associates C and D were optimized as local minima, however, in these conformers, both

enantiotopic faces of the imine C=N bond are well shielded by the two TPH substituents.

Table II: Computational data for the hydrogen-bonding pairs of (R)-1b/3a complexes

Conformer Relative energy [kcal/mol] re-face[a] si-face[a]

A 0.00 inaccessible inaccessible

B 1.58 fully accessible inaccessible

C 0.70 inaccessible inaccessible

D 1.13 inaccessible inaccessible [a] Accessibility to the imine C=N bond.

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A (0.00 kcal/mol) B (1.58 kcal/mol)

C (0.70 kcal/mol) D (1.13 kcal/mol)

Figure II. 3D structures for the optimized geometries (at the B3LYP/6-31G** level of theory) of the

hydrogen-bonding pairs of (R)-1b (G = TPH) with 3a. A: The lowest energy conformer of (R)-1b/3a complex;

B-D: Local minima of the (R)-1b/3a complex. The nucleophile (indole) is accessible to the re-face of the imine (3a)

in complex B (blue arrow), leading to (S)-4 product.

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7.2. Computational Analysis of Hydrogen-Bonding Pairs, (R)-1b/3a Complexes:

Inspection of Table III and Figure III shows that the lowest energy conformer E optimized from associate

(R)-1a/3a closely resembles the catalytically active associate B from (R)-1b/3a (Figure II) in terms of the relative

placement of the imine and the phosphoric acid moiety. In the associates B and E, the aromatic moieties of the

imine orient towards the side of the phosphoryl oxygen and hydrogen bonding occurs between the aromatic ortho

C-H and O=P. However, in associate E, both enantiotopic faces of the imine are completely shielded by the

sterically demanding HMT substituents, in which the ortho methyl substituents enforce the mesityl ring perpendicular

to the basal phenyl moiety. After further computational analysis of the 1a/3 hydrogen-bonding pairs it was found

that associate F was optimized to provide the (R)-product. The bottom side of the associated imine is completely

open to approach by the nucleophile (blue arrow indicated in F). The associate F is energetically unfavorable as

compared to E, and hence the low catalytic activity observed in the reaction by 1a might be ascribed to the low

population of the catalytically active associates related to F. Several conformers of 1a/3 with local minima were

also obtained. One of these, conformer G, had the si-face of the imine accessible, leading to the opposite

enantiomer, the (S)-product. The moderate enantioselectivity observed for (R)-1a is presumably due to a part of the

reaction to proceed through this associate G.

Table III: Computational data for the hydrogen-bonding pairs of (R)-1a/3a complexes

Conformer Relative energy [kcal/mol] re-face[a] si-face[a]

E 0.00 inaccessible inaccessible

F 2.23 inaccessible fully accessible

G 2.23 fairly accessible inaccessible

[a] Accessibility to the imine C=N bond.

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E (0.00 kcal/mol) F (2.23 kcal/mol)

G (2.23 kcal/mol)

Figure III. 3D structures for the optimized geometries (at the B3LYP/6-31G** level of theory) of the

hydrogen-bonding pairs of (R)-1a (G = HMT) with 3a. E: The lowest energy conformer of the (R)-1a/3a complex;

F-G: Local minima of the (R)-1a/3a complex. The nucleophile (indole) is accessible to the si-face of the imine (3a)

in complex F (blue arrow), leading to (R)-4 product. The nucleophile (indole) is fairly accessible to the re-face of

the imine (3a) in complex G (blue arrow), leading to (S)-4 product.