doi: 10.

1038/nature08484

SUPPLEMENTARY INFORMATION

Scaleable catalytic asymmetric Strecker syntheses of

unnatural α-amino acids

Stephan J. Zuend, Matthew P. Coughlin, Mathieu P. Lalonde & Eric N. Jacobsen

Harvard University, Department of Chemistry & Chemical Biology, Cambridge, MA 02138.

Supplementary Methods

General Experimental Procedures. Reactions were carried out in oven-dried round-bottomed flasks, unless

otherwise noted. The flasks were fitted with rubber septa and reactions were conducted under a positive pressure of

nitrogen. Stainless steel syringes or cannulae were used to transfer air- and moisture-sensitive liquids. Flash

chromatography was performed using silica gel 60 (230-400 mesh) from EM Science.

Materials. Commercial reagents were purchased from Sigma Aldrich, Alfa Aesar, or Lancaster, and used as

received with the following exceptions: dichloromethane and toluene were dried by passing through columns of

activated alumina. Diisopropylethylamine and triethylamine were distilled from CaH2 at 760 torr. TMSCN was

distilled at 760 Torr and stored in a Schlenk flask at 0 ºC.

Instrumentation. Proton nuclear magnetic resonance (1H NMR) spectra and carbon nuclear magnetic resonance

(13C NMR) spectra were recorded on Varian-Mercury-400 (400 MHz) or Inova-500 (500 MHz) spectrometers.

Chemical shifts for protons are reported in parts per million downfield from tetramethylsilane and are referenced to

residual protium in the NMR solvent (CHCl3: δ 7.26) Chemical shifts for carbon are reported in parts per million

downfield from tetramethylsilane and are referenced to the carbon resonances of the solvent (CDCl3: δ 77.16). Data

are represented as follows: chemical shift, integration, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q

= quartet, m = multiplet), coupling constants in Hertz (Hz). Infrared (IR) spectra were obtained using a Mattson

Galaxy Series FTIR 3000 spectrophotometer referenced to a polystyrene standard. Data are represented as follows:

frequency of absorption (cm-1), intensity of absorption (s = strong, m = medium, w = weak, br = broad). Optical

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rotations were measured using a 2-mL cell with a 10-cm path length on a Jasco DIP 370 digital polarimeter. The

mass spectral data were obtained at the Harvard University mass spectrometry facility. Chiral HPLC analysis was

performed using a Shimadzu VP-series instrument.

Preparation of amido-thiourea catalysts31

(S)-tert-butyl 1-(benzhydryl(methyl)amino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate:

An oven-dried 50-mL round-bottomed flask was charged with Boc-L-tert-leucine (2.78 g, 12.0 mmol, 1.0 equiv),

HBTU (5.01 g, 13.2 mmol, 1.1 equiv), and N-(diphenylmethyl)methylamine (3.55 g, 18 mmol, 1.5 equiv).

Anhydrous CH2Cl2 (24 mL) and N,N-diisopropylethylamine (4.18 mL, 24 mmol, 2.0 equiv) were added sequentially

via syringe. The flask was capped with a plastic stopper, and the reaction mixture was stirred for 3 days at room

temperature. The resulting orange mixture was diluted with Et2O (100 mL), washed with 1 N HCl (2 x 100 mL),

sat. NaHCO3 (100 mL), and brine (100 mL). The organic phase was dried over Na2SO4 and concentrated under

reduced pressure to provide a viscous orange oil. The product was subjected to purification by flash column

chromatography on silica gel (gradient elution, 19:1 → 1:1 hexanes/Et2O, 100 g silica gel, 1.2 L solvent) to provide

the product as a white foam (4.51 g, 11.0 mmol, 91% yield). [α ]D = –28.2° (c 1.76, CHCl3). The compound exists
25

1
as a 5:1 mixture of amide rotamers in CDCl3. H NMR (500 MHz, CDCl3), major rotamer: δ 7.38-7.14 (11H, m),

5.28 (1H, d, J = 10.0 Hz), 4.57 (1H, d, J = 10.0 Hz), 2.97 (3H, s), 1.46, (9H, s), 1.03 (9H, s); minor rotamer: δ 7.38-

7.14 (10H, m), 6.77 (1H, s), 5.28 (1H, d, J = 10.0 Hz), 4.72 (1H, d, J = 10.0 Hz), 2.73, (3H, s), 1.44 (9H, s), 0.93
13
(9H, s). C{1H} NMR (126 MHz, CDCl3), major rotamer: δ 173.0, 156.2, 139.3, 138.4, 129.4, 128.5, 128.4, 127.9,

31
Catalysts were prepared by a modification of the literature procedure: Reisman, S. E., Doyle, A. G. & Jacobsen,
E. N. Enantioselective thiourea-catalyzed additions to oxocarbenium ions. J. Am. Chem. Soc. 130, 7198–7199
(2008). The preparation of catalysts not described herein has been reported previously by Reisman et al.

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127.6, 127.1, 79.6, 60.8, 56.7, 35.2, 33.2, 28.3, 26.5; minor rotamer: δ 173.5, 155.5, 139.4, 138.8, 129.0, 128.5,

128.4, 128.3, 127.7, 127.6, 79.5, 64.6, 56.1, 35.3, 31.3, 28.3, 26.5. IR (cm-1): 3436 (w), 3326 (w), 3062 (w), 3029

(w), 2965 (m), 2871 (w), 1953 (w), 1893(w), 1810 (w), 1712 (s), 1640 (s), 1496 (s), 1454 (m), 1404 (m), 1366 (m),

1320 (w), 1245 (m), 1172 (s), 1105 (w), 1058 (w), 1005 (w), 974 (w), 922 (w), 870 (w), 734 (w), 702 (m), 608 (w).
+
LRMS (ESI): 433.25 (100%) [M+Na] .

(S)-2-amino-N-benzhydryl-N,3,3-trimethylbutanamide:

A 200-mL round-bottomed flask containing (R)-tert-butyl 1-(benzhydryl(methyl)amino)-3,3-dimethyl-1-oxobutan-

2-ylcarbamate (4.51 g, 11.0 mmol, 1 equiv) and a stir bar was purged with N2. Anhydrous CH2Cl2 (55 mL) and

triethylamine (3.07 mL, 22.0 mmol, 2 equiv) were added sequentially via syringe. The reaction was cooled to 0 °C

in an ice bath, and trimethylsilyl trifluoromethansulfonate (18.8 mL, 110 mmol, 10 equiv) was added dropwise via

syringe over 5 min with stirring. The solution was stirred for 1 h at 0 °C. The slightly yellow homogeneous

reaction mixture was treated with 100 mL of ice cold saturated aqueous NaHCO3 in 10-mL portions over 5 min at 0

°C. The mixture was transferred to a 500-mL separatory funnel, and diluted with saturated aqueous NaHCO3 (100

mL) and CH2Cl2 (50 mL). The layers were thoroughly mixed with venting, and the organic layer was removed. The

aqueous layer was extracted with CH2Cl2 (50 mL). The combined organic layers were dried over Na2SO4, decanted

into a 500-mL round-bottomed flask, and concentrated in vacuo to provide a viscous yellow residue. The residue

was partitioned between CH2Cl2 (50 mL) and saturated NaHCO3 (50 mL). The aqueous layer was extracted with

CH2Cl2 (30 mL). The organic layers were dried over Na2SO4 and filtered through a 2-cm height pad of silica gel on

a 5-cm diameter fritted disk funnel, rinsing with CH2Cl2 (30 mL). The receiving flask was switched, and the silica

gel pad was further eluted with 1:1:0.04 CH2Cl2/Et2O/MeOH (200 mL) to provide the product as a yellow oil in

>95% 1H-NMR purity (2.98 g, 9.60 mmol, 87% yield). The product was used in the next step without further

purification. Spectroscopically pure product may be isolated by subjecting the crude product to flash column

chromatography on silica gel (gradient elution, 3:1 CH2Cl2/Et2O Æ 1:1:0.05 CH2Cl2/Et2O/MeOH). The compound
1
exists as a 3.5:1 mixture of amide rotamers in CDCl3. H NMR (500 MHz, CDCl3), major rotamer: δ 7.14–7.34

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(11H, m), 3.59 (1H, s), 2.88 (3H, s), 1.54 (2H, br s), 1.02 (9H, s); minor rotamer: δ 7.34-7.14 (10H, m), 6.53 (1H, s),
13
3.47 (1H, s), 2.72 (3H, s), 1.54 (2H, br s), 1.03 (9H, s). C{1H} NMR (125 MHz, CDCl3), major rotamer: δ 175.4,

139.2, 138.8, 129.1, 128.44, 128.40, 128.3, 127.4, 127.2, 60.4, 58.4, 35.6, 32.9, 26.4; minor rotamer: δ 176.5, 139.6,

139.0, 128.9, 128.8, 128.5, 127.9, 127.82, 127.79, 64.5, 58.5, 34.9, 31.3, 26.6. IR (cm-1): 3381 (w), 3307 (w), 3061

(m), 3029 (m), 2955 (s), 2867 (m), 1955 (w), 1892 (w), 1813 (w), 1768 (w), 1639 (s), 1495 (s), 1479 (m), 1447 (m),

1409 (m), 1364 (m), 1282 (m), 1104 (m), 1079 (m), 1031 (m), 970 (m), 922 (m), 870 (m), 827 (m), 762 (m), 735
+
(m), 701 (s). LRMS (ESI): 311.2126 (100%), [C20H26N2O+H] .

(S)-N-benzhydryl-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N,3,3-trimethylbutanamide (4e):

A 100-mL round-bottomed flask containing (S)-2-amino-N-benzhydryl-N,3,3-trimethylbutanamide (2.98 g, 9.60

mmol, 1.0 equiv) was charged with anhydrous CH2Cl2 (30 mL). 3,5-Bis(trifluoromethyl)phenylisothiocyanate (1.75

mL, 9.60 mmol, 1.0 equiv) was added in one portion via syringe. The flask was capped with a plastic stopper, and

the reaction mixture was stirred for 2 h at room temperature. The clear, yellow solution was concentrated using a

rotary evaporator. The residue was subjected to purification by flash column chromatography on silica gel (gradient

elution, hexanes → 1:1 hexanes/Et2O, 100 g silica gel, 1.5 L solvent). The product was isolated as a white solid in

~98% 1H-NMR purity (5.14 g, 8.83 mmol, 92% yield; 74% yield over three steps). The compound exists as a 15:1
1
mixture of amide rotamers in CDCl3. [α ]D = –83.4° (c 1.0, CHCl3). H NMR (500 MHz, CDCl3), major rotamer: δ
25

8.26 (1H, br s), 8.92 (1H, br s), 7.69 (2H, s), 7.59 (1H, s), 7.31–7.37 (3H, m), 7.13–7.16 (2H, m), 6.95–7.06 (5H, m),

5.65 (1H, d, J = 9 Hz), 3.13 (3H, s), 1.13 (9H, s); selected minor rotamer resonances: δ 2.76 (3H, s), 0.92 (9H, s).
13
C{1H} NMR, major rotamer: δ 182.5, 174.2, 139.7, 139.0, 137.3, 131.9 (q, JC-F = 34 Hz), 129.8, 128.8, 128.7,

128.4, 128.2, 127.5, 127.2, 126.3 (m), 123.1 (q, JC-F = 274 Hz), 119.3 (m), 62.4, 62.3, 36.5, 34.0, 27.6. IR (cm-1):

3313 (br m), 2967 (m), 1609 (m), 1529 (m), 1473 (m), 1380 (m), 1276 (s), 1172 (m), 1127 (s), 961 (m), 889 (w),
+
847 (w), 758 (w), 698 (m), 681 (m). LRMS (ESI): 582.2 (80%) [M+H] .

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9 8 7 6 5 4 3 2 1 0
Chemical Shift (ppm)

Supplementary Figure 1. 1H NMR spectrum of 4e.

180 160 140 120 100 80 60 40 20 0

Chemical Shift (ppm)

Supplementary Figure 2. 13C NMR spectrum of 4e.

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(S)-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N,N,3,3-tetramethylbutanamide (4a):

A 50-mL round-bottomed flask was charged with (S)-tert-butyl 1-(dimethylamino)-3,3-dimethyl-1-oxobutan-2-

ylcarbamate32 (860 mg, 2.0 mmol, 1.0 equiv) and 4 N HCl in dioxane (5.0 mL). The reaction mixture was stirred at

room temperature for 2 h, then concentrated under reduced pressure and maintained at ~ 1 torr for 1 h. The resulting

white, foamy solid was dissolved in CH2Cl2 (10 mL). Et3N (562 μL, 4.0 mmol, 2.0 equiv) and 3,5-

bis(trifluoromethyl)phenylisothiocyanate (596 mg, 2.2 mmol, 1.1 equiv) were added sequentially via syringe. The

flask was capped with a plastic stopper, and the reaction mixture was stirred at room temperature for 14 h. The

reaction mixture was concentrated under reduced pressure, and the residue was subjected to purification by flash

column chromatography on silica gel (gradient elution, 3:1 hexanes/Et2O → 1:1 hexanes/Et2O) to provide the
1
product as a white solid (613 mg, 1.43 mmol, 71% yield over two steps). [α ]D = –32.8° (c 1.0, CHCl3). H NMR
25

(500 MHz, CDCl3): δ 9.06 (1H, s), 7.90 (2H, s), 7.77 (1H, d, J = 9 Hz), 7.56 (1H, s), 5.68 (1H, d, J = 9 Hz), 3.35
13
(3H, s), 2.97 (3H, s), 1.12 (9 H, s). C{1H} NMR (100 MHz, CDCl3): δ 181.8, 174.0, 140.3, 131.7 (q, JC-F = 33

Hz), 123.7 (m), 123.3 (q, JC-F = 272 Hz), 118.1 (m), 60.9, 39.1, 36.2, 36.0, 27.2. IR (cm-1): 3322 (br m), 2972 (m),

1611 (m), 1532 (s), 1474 (m), 1385 (m), 1274 (s), 1174 (m), 1126 (s), 963 (m), 883 (m), 848 (w), 700 (m), 680 (m).
+
LRMS (ESI): 452.1 (60%) [M+Na] .

32
The preparation of (S)-tert-butyl 1-(dimethylamino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate has been reported:
Vachal, P. & Jacobsen, E. N. Structure-based analysis and optimization of a highly enantioselective catalyst for the
Strecker reaction J. Am. Chem. Soc. 124, 10012–10014 (2002).

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Preparation of imines

Method A: A 250-mL round-bottomed flask was charged with dichloromethane (80 mL), anhydrous Na2SO4 (30 g),

aminodiphenylmethane (12 mmol), and aldehyde (12 mmol). The mixture was stirred at room temperature until the

aldehyde had been fully consumed, as determined by 1H NMR analysis of an aliquot removed from the reaction

mixture (1–12 h). The mixture was filtered through a fritted disk funnel, rinsing with dichloromethane (3 x 10 mL).

A 3” plug of silica gel was was rinsed with 9:1:0.1 hexanes/diethyl ether/triethylamine (100 mL). The reaction

mixture was concentrated under reduced pressure, and the crude residue was filtered through the silica gel plug with

9:1 hexanes/diethyl ether as the eluent. The filtrate was concentrated under reduced pressure to provide the imine

product (> 90% yield). The imine was used in the next step without further purification.

Method B: A 100-mL round-bottomed flask was charged with toluene (40 mL), aminodiphenylmethane (12 mmol),

and aldehyde (12 mmol). A Dean-Stark trap was attached to the flask, and the mixture was stirred at reflux under N2

in an oil bath until the aldehyde was fully consumed, as determined by 1H NMR analysis of an aliquot removed from

the reaction mixture. A 3” plug of silica gel was rinsed with 9:1:0.1 hexanes/diethyl ether/triethylamine (100 mL).

The reaction mixture was concentrated under reduced pressure, and the crude residue was filtered through a the

silica gel plug with 9:1 hexanes/diethyl ether as the eluent. The filtrate was concentrated under reduced pressure to

provide the imine product (> 90% yield). The imine was used in the next step without further purification.

(E)-N-(2,2-dimethylpropylidene)diphenylmethanamine (2a):

Prepared via Method A. Spectroscopic data match previously reported data.33

(E)-N-(2-ethyl-2-methylbutylidene)diphenylmethanamine (2b):34

33
Krueger, C. A., Kuntz, K. W., Dzierba, C. D., Wirschun, W. G., Gleason, J. D., Snapper, M. L. & Hoveyda, A. H.
Ti-catalyzed enantioselective addition of cyanide to imines. A practical synthesis of optically pure alpha-amino
acids. J. Am. Chem. Soc. 121, 4284–4285 (1999).
34
The preparation of the aldehyde precursor of this imine is described in Section 6.

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Prepared via Method A. 1H NMR (500 MHz, CDCl3): δ 7.70 (1H, s), 7.43 (4H, d, J = 7.5 Hz), 7.38 (4H, t, J = 7.8

Hz), 7.29 (2H, t, J = 7.3 Hz), 5.47 (1H, s), 1.52-1.65 (4H, m), 1.16 (3H, s), 0.87 (6H, t, J = 7.8 Hz). 13C{1H} NMR

(125 MHz, CDCl3): δ 171.2, 144.3, 128.2, 127.5, 126.6, 77.8, 42.5, 30.6, 20.6, 8.4. IR (cm-1): 3061 (w), 3026 (w),

2925 (m, br), 2850 (m, br), 1661 (m), 1493 (m), 1449 (m), 1026 (m), 756 (m), 696 (s). LRMS (ESI): 292.2 (100%)

[M+H]+.

(E)-N-(2-methyl-2-phenylpropylidene)diphenylmethanamine (2c):35

Prepared via Method B. 1H NMR (500 MHz, CDCl3): δ 7.90 (1H, s), 7.44 (4H, d, J = 8.0 Hz), 7.27-7.40 (11H, m),
13
5.49 (1H, s), 1.60 (6H, s). C{1H} NMR (125 MHz, CDCl3): δ 169.4, 145.9, 144.1, 128.4, 128.3, 127.5, 126.8,

126.4, 126.3, 77.3, 44.0, 26.1. IR (cm-1): 3060 (w), 3026 (w), 2969 (w), 2836 (w), 1660 (m), 1599 (w), 1493 (m),

1448 (m), 1387 (w), 1364 (w), 1028 (m), 762 (m), 696 (s). LRMS (ESI): 314.2 (100%) [M+H]+.

(E)-N-((1-methylcyclohexyl)methylene)diphenylmethanamine (2d):34

Prepared via Method B. 1H NMR (500 MHz, CDCl3): δ 7.74 (1H, s), 7.43 (4H, d, J = 6.5 Hz), 7.38 (4H, t, J = 7.5

Hz), 7.29 (2H, t, J = 7.3 Hz), 5.44 (1H, s), 1.89-1.93 (2H, m), 1.49-1.62 (5H, m), 1.38-1.43 (3H, m), 1.13 (3H, s).
13
C{1H} NMR (125 MHz, CDCl3): δ 171.6, 144.3, 128.3, 128.1, 127.6, 127.5, 126.7, 77.8, 39.6, 35.6, 26.0, 25.5,

22.5. IR (cm-1): 3062 (w), 3026 (w), 2965 (m, br), 2935 (m), 1661 (m), 1599 (w), 1492 (m), 1452 (m), 1382 (m),

1030 (m), 745 (m), 696 (s). LRMS (ESI): 280.2 (100%) [M+H]+.

35
For the preparation of 2-methyl-2-phenylpropanal, see: Dudnik, A. S., Schwier, T. & Gevorgyan, V. Gold-
catalyzed double migration-benzannulation cascade toward napthalenes. Org. Lett. 10, 1465–1468 (2008).

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(E)-N-(1-adamantyl)diphenylmethanamine (2e):36

Prepared via Method A. 1H NMR (500 MHz, CDCl3): δ 7.56 (1H, s), 7.31-7.35 (8H, m), 7.22-7.27 (2H, m), 5.34

(1H, s), 2.06 (3H, s), 1.72-1.79 (12H, m). 13C{1H} NMR (125 MHz, CDCl3): δ 171.6, 144.3, 128.3, 127.5, 126.7,

77.5, 39.5, 38.4, 36.8, 28.1. IR (cm-1): 3024 (w), 2905 (m, br), 2849 (m), 2798 (m), 1661 (m), 1492 (m), 1449 (m),

1053 (m), 750 (m), 699 (s). LRMS (ESI): 330.2 (100%) [M+H]+.

(E)-N-(cyclohexylmethylene)diphenylmethanamine (2f):

Prepared via Method A. 1H NMR (500 MHz, CDCl3): δ 7.65 (1H, d, J = 5.0 Hz), 7.23-7.26 (8H, m), 7.15-7.18 (2H,

m), 5.27 (1H, s), 2.24-2.27 (1H, m), 1.80-1.83 (2H, m), 1.70 - 1.72 (2H, m), 1.61-1.64 (1H, m), 1.15-1.29 (5H, m).
13
C{1H} NMR (125 MHz, CDCl3): δ 169.1, 144.0, 128.3, 127.6, 126.8, 77.9, 43.5, 29.7, 26.0, 25.4. IR (cm-1) 3060

(w), 3026 (w), 2932 (m), 2852 (m), 1664 (m), 1493 (m), 1448 (m), 1376 (w), 1276 (w), 1016 (w), 890 (w), 759 (m),

745 (s), 697 (s). LRMS (ESI): 278.2 (50%) [M+H]+.

(E)-N-(4-methoxybenzylidene)diphenylmethanamine (2g):

Prepared via Method A. Spectroscopic data match previously reported data.33

(E)-N-(4-methylbenzylidene)diphenylmethanamine (2h):

36
For the preparation of 1-adamantanecarboxaldehyde, see: Augeri, D. J. et. al. Discovery and preclinical profile of
Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the
treatment of type 2 diabetes. J. Med. Chem. 48, 5025–5037 (2005).

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Prepared via Method A. 1H NMR (500 MHz, CDCl3): δ 8.47 (1H, s), 7.82 (2H, d, J = 8.0 Hz), 7.50 (4H, m), 7.40

(4H, m), 7.31 (4H, m), 5.67 (1H, s), 2.46 (3H, s). 13C{1H} NMR (125 MHz, CDCl3): δ 160.6, 144.0, 141.0, 133.7,

129.2, 128.4, 128.4, 127.7, 126.9, 77.8, 21.5. IR (cm-1): 3081 (w), 3026 (w), 2919 (w), 2851 (w), 1663 (m), 1491

(m), 1274 (m), 1027 (m), 817 (m), 756 (m), 733 (m), 697 (s). LRMS (ESI): 286.2 (100%) [M+H]+.

(E)-N-benzylidenediphenylmethanamine (2i):

Prepared via Method A. Spectroscopic data match previously reported data.33

(E)-N-(4-chlorobenzylidene)diphenylmethanamine (2j):

Prepared via Method A. Spectroscopic data match previously reported data.37

(E)-diphenyl-N-(4-(trifluoromethyl)benzylidene)methanamine (2k):

Prepared via Method A. 1H NMR (500 MHz, CDCl3): δ 8.50 (1H, s), 7.99 (2H, d, J = 8.0 Hz), 7.71 (2H, d, J = 8.0

Hz), 7.45 (4H, d, J = 8.0 Hz), 7.38 (4H, t, J = 7.8 Hz), 7.29 (2H, t, J = 7.5 Hz), 5.69 (1H, s). 13C{1H} NMR (125

37
Lautens, M., Tayama, E. & Nguyen, D. Direct vinylogous Mannich-type reactions via ring opening and
rearrangement of vinyloxiranes. Org. Lett. 6, 345–347 (2004).

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MHz, CDCl3): δ 159.3, 143.5, 139.4, 132.3 (q, JC-F = 32.2 Hz), 128.6, 128.5, 127.6, 127.2, 125.5 (q, JC-F = 3.6 Hz),

123.9 (q, JC-F = 271.3 Hz), 78.0. IR (cm-1): 2981 (w), 1637 (w), 1320 (m), 1131 (s), 1064 (m), 834 (m), 739 (m), 695

(s). LRMS (ESI): 340.1 (100%) [M+H]+.

(E)-4-((benzhydrylimino)methyl)benzonitrile (2l):

Prepared via Method A. 1H NMR (500 MHz, CDCl3): δ 8.48 (1H, s), 7.96 (2H, d, J = 8.0 Hz), 7.72 (2H, d, J = 8.5

Hz), 7.44-7.46 (4H, m), 7.37-7.42 (4H, m), 7.29-7.32 (2H, m), 5.70 (1H, s). 13C{1H} NMR (125 MHz, CDCl3): δ

158.9, 143.2, 140.0, 132.3, 128.8, 128.5, 128.3, 127.5, 127.2, 118.5, 114.0, 78.0. IR (cm-1): 3064 (w), 3023 (w),

2874 (w), 2852 (w), 2222 (m), 1634 (m), 1490 (m), 1451 (m), 1378 (m), 1025 (m), 855 (m), 829 (m), 752 (s), 702

(s). LRMS (ESI): 297.1 (30%) [M+H]+.

(E)-N-(4-bromobenzylidene)diphenylmethanamine (2m):

Prepared via Method A. 1H NMR (500 MHz, CDCl3): δ 8.41 (1H, s), 7.74-7.76 (2H, m), 7.58-7.60 (2H, m), 7.44-

7.45 (4H, m), 7.34-7.39 (4H, m), 7.27-7.30 (2H, m), 5.64 (1H, s). 13C{1H} NMR (125 MHz, CDCl3): δ 159.5, 143.6,

135.2, 131.7, 129.8, 128.4, 127.6, 127.0, 125.1, 77.8. IR (cm-1): 3062 (w), 3023 (w), 2856 (m), 1638 (m), 1567 (m),

1484 (m), 1068 (m), 1012 (m), 812 (m), 744 (m), 698 (s). LRMS (ESI): 350.1 (60%) [M+H]+.

(E)-N-(2-methoxybenzylidene)diphenylmethanamine (2n):

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Prepared via Method A. 1H NMR (500 MHz, CDCl3): δ 8.99 (1H, s), 8.26 (1H, dd, J = 1.8, 7.8 Hz), 7.48-7.50 (4H,

m), 7.38 (4H, t, J = 7.5 Hz), 7.27-7.30 (2H, m), 7.06 (1H, t, J = 7.3 Hz), 6.96 (1H, d, J = 8.5 Hz), 5.67 (1H, s), 3.89

(3H, s). 13C{1H} NMR (125 MHz, CDCl3): δ 158.8, 156.6, 144.3, 131.9, 128.3, 127.7, 127.6, 126.8, 124.7, 120.7,

110.9, 78.4, 55.4. IR (cm-1): 3079 (w), 3020 (w), 2938 (w), 2837 (w), 1631 (m), 1598 (m), 1487 (m), 1378 (m), 1175

(m), 1080 (m), 775 (s), 739 (s), 697 (s). LRMS (ESI): 302.2 (100%) [M+H]+.

(E)-N-(2-bromobenzylidene)diphenylmethanamine (2o):

Prepared via Method A. Spectroscopic data match previously reported data.33

(E)-N-(3-bromobenzylidene)diphenylmethanamine (2p):

Prepared via Method A. 1H NMR (500 MHz, CDCl3): δ 8.39 (1H, s), 8.09 (1H, m), 7.73 (1H, dd, J = 1.3, 7.8 Hz),

7.56-7.59 (1H, m), 7.44 (4H, d, J = 7.0 Hz), 7.37 (4H, t, J = 7.8Hz), 7.27-7.32 (3H, m), 5.65 (1H, s). 13C{1H} NMR

(125 MHz, CDCl3): δ 159.2, 143.5, 138.2, 133.6, 130.9, 130.0, 128.5, 127.6, 127.3, 127.1, 122.8, 77.8. IR (cm-1):

3057 (w), 3026 (w), 2839 (m), 1658 (m), 1565 (m), 1492 (m), 1447 (m), 1381 (m), 1210 (m), 1024 (m), 787 (m),

759 (m), 741 (s), 697 (s). LRMS (ESI): 350.1 (60%) [M+H]+.

(E)-N-(furan-2-ylmethylene)diphenylmethanamine (2q):

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Prepared via Method A. Spectroscopic data match previously reported data.38

(E)-N-(furan-3-ylmethylene)diphenylmethanamine (2r):

1
Prepared via Method A. H NMR (500 MHz, CDCl3): δ 8.36 (1H, s), 7.74 (1H, s), 7.44-7.45 (1H, m), 7.38-7.40
13
(4H, m), 7.33-7.36 (4H, m), 7.24-7.28 (2H, m), 6.95 (1H, s), 5.57 (1H, s). C{1H} NMR (125 MHz, CDCl3): δ

152.5, 145.3, 143.9, 143.7, 128.4, 127.7, 127.0, 125.7, 108.2, 77.9. IR (cm-1): 3082 (w), 3051 (w), 1644 (m), 1511

(m), 1492 (m), 1153 (m), 1076 (m), 1017 (m), 774 (m), 745 (m), 726 (m), 698 (s). LRMS (ESI): 262.1 (80%)

[M+H]+.

(E)-diphenyl-N-(thiophen-2-ylmethylene)methanamine (2s):

Prepared via Method A. 1H NMR (500 MHz, CDCl3): δ 8.52 (1H, s), 7.44-7.46 (5H, m), 7.36-7.40 (5H, m), 7.28-

7.31 (2H, m), 7.10 (1H, dd, J = 3.5, 5.0 Hz), 5.66 (1H, s). 13C{1H} NMR (125 MHz, CDCl3): δ 154.0, 143.6, 142.7,

130.6, 129.1, 128.4, 127.7, 127.3, 127.0, 77.1. IR (cm-1): 3103 (w), 3061 (w), 2848 (w), 1626 (m), 1491 (m), 1430

(m), 1218 (m), 1022 (m), 758 (m), 748 (m), 699 (s). LRMS (ESI): 278.1 (100%) [M+H]+.

(E)-N-(cyclohexenylmethylene)diphenylmethanamine (2t):

38
Cainelli, G., Giacomini, D., Trer, A. & Boyl, P. P. Efficient transamination under mild conditions: Preparation of
primary amine derivatives from carbonyl compounds via imine isomerization with catalytic amounts of potassium
tert-butoxide. J. Org. Chem. 61, 5134–5139 (1996).

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Prepared via Method A. 1H NMR (500 MHz, CDCl3): δ 7.98 (1H, s), 7.39-7.41 (4H, m), 7.33-7.36 (4H, m), 7.24-

7.28 (2H, m), 6.20 (1H, apparent sextet, J = 1.8 Hz), 5.46 (1H, s), 2.48-2.50 (2H, m), 2.23-2.26 (2H, m), 1.68-1.74

(4H, m). 13C{1H} NMR (125 MHz, CDCl3): δ 163.9, 144.4, 138.9, 138.4, 128.3, 127.6, 126.7, 77.6, 26.1, 23.9, 22.5,

22.0. IR (cm-1): 3069 (w), 3022 (w), 2932 (m br), 2848 (w), 1643 (m), 1627 (m), 1491 (m), 1448 (m), 1376 (m),

1087 (m), 745 (m), 697 (s). LRMS (ESI): 276.2 (100%) [M+H]+.

(E)-N-((E)-2-methylpent-2-enylidene)diphenylmethanamine (2u):

Prepared via Method A. 1H NMR (500 MHz, CDCl3): δ 8.03 (1H, s), 7.45 (4H, d, J = 8.0 Hz), 7.39 (4H, t, J = 7.8

Hz), 7.29 (2H, tt, J = 1.6, 7.3 Hz), 5.94 (1H, td, J = 1.6, 7.5 Hz), 5.52 (1H), 2.33 (2H, p, J = 7.5 Hz), 2.05 (3H, s),

1.12 (3H, t, J = 7.5 Hz). 13C{1H} NMR (125 MHz, CDCl3): δ 165.2, 144.4, 143.8, 135.7, 128.3, 128.3, 128.1, 127.6,

127.5, 126.8, 126.7, 77.5, 21.8, 13.4, 11.6. IR (cm-1): 3061 (w), 3026 (w), 2966 (w), 2932 (w), 2872 (w), 1626 (m),

1492 (m), 1451 (m), 1051 (m), 1030 (m), 740 (m), 696 (s). LRMS (ESI): 264.2 (100%) [M+H]+.

(E)-diphenyl-N-((E)-3-phenylallylidene)methanamine (2v):

Prepared via Method A. 1H NMR (500 MHz, CDCl3): δ 8.24 (1H, d, J = 8.5 Hz), 7.52-7.53 (2H, m), 7.36-7.42

(11H, m), 7.27-7.30 (2H, m), 7.13 (1H, dd, J = 8.8, 16.3 Hz), 7.01 (1H, d, J = 16.0 Hz), 5.54 (1H, s). 13C{1H} NMR

(125 MHz, CDCl3): δ 162.8, 143.6, 142.3, 135.7, 129.2, 128.8, 128.4, 128.3, 127.7, 127.2, 127.0, 78.2. IR (cm-1):

3080 (w), 3026 (w), 2851 (w), 1630 (m), 1489 (m), 1446 (m), 1151 (m), 997 (m), 964 (m), 742 (s), 692 (s). LRMS

(ESI): 298.2 (100%) [M+H]+.

(E)-N-((E)-hex-2-enylidene)diphenylmethanamine (2w):

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Prepared via Method A. 1H NMR (500 MHz, CDCl3): δ 8.07 (1H, d, J = 8.8 Hz), 7.35-7.41 (8H, m), 7.26-7.30 (2H,

m), 6.46 (1H, dd, J = 8.8, 15.6 Hz), 6.27 (1H, dt, J = 6.7, 15.5 Hz), 5.45 (1H, s), 2.25 (2H, q, J = 7.1 Hz), 1.54 (2H,

sextet, J = 7.4 Hz), 1.00 (3H, t, J = 7.4 Hz). 13C{1H} NMR (125 MHz, CDCl3): δ 162.9, 146.3, 143.7, 130.7, 128.3,

127.6, 126.8, 78.0, 34.6, 21.6, 13.6. IR (cm-1): 3061 (w), 3026 (w), 2959 (w), 2929 (w), 2871 (w), 1652 (m), 1492

(m), 1451 (m), 1028 (m), 989 (m), 961 (m), 741 (s), 697 (s). LRMS (ESI): 264.2 (100%) [M+H]+.

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Hydrocyanation of imines using TMSCN and MeOH

Caution! HCN is produced. The experiment should be executed in a well-ventilated fume hood. A flame-dried 25-

mL round-bottomed flask containing a stir bar was charged with imine (1.0 mmol, 1.0 equiv) and (S)-N-benzhydryl-

2-(3-(3,5-bis(trifluoromethyl)phenyl) thioureido)-N,3,3-trimethylbutanamide (4e) (11.6 mg, 0.02 mmol, 0.02 equiv).

The flask was capped with a virgin rubber septum and flushed with N2. Toluene (3.75 mL) was added via syringe

under N2, and the mixture was stirred at room temperature until a homogenous solution formed. The flask was then

cooled in a dry ice/acetone (–78 °C) bath for 10 min. A stock solution of HCN was prepared as follows: a flame-

dried 10-mL round-bottomed flask containing a stir bar was capped with a virgin septum. Toluene (1.25 mL) was

added via syringe under N2, and the flask was cooled in an ice-water bath for 10 min. TMSCN (0.27 mL, 2.0 mmol,

2.0 equiv) was added via syringe. Methanol (0.075 mL, 1.9 mmol, 1.9 equiv) was then added over 90 s with

stirring. The stock solution was stirred at 0 °C for 30 min and then added via syringe to reaction mixture over a

period of two minutes with stirring. The reaction flask was sealed with Parafilm, transferred to either a –30 °C

freezer or 0 °C refrigerator, and aged for 20 h. After 20 h, the reaction flask was transferred to a well-ventilated

fume hood, and the reaction mixture was concentrated under reduced pressure (1 torr). The residue was subjected to

purification by flash column chromatography with Et2O/hexanes as the eluent.

α-Aminonitriles that are solids can show enantiomeric enrichment upon crystallization. All solid α-aminonitriles

were homogenized using a metal spatula prior to chiral HPLC analysis to ensure that an accurate measurement of

enantioselectivity was obtained. Samples that were not mechanically homogenized yielded inconsistent

enantiomeric excess values in the chiral HPLC analysis.

(R)-2-(benzhydrylamino)-3,3-dimethylbutanenitrile (3a):

The reaction was run at –30 °C for 20 h without stirring using (E)-N-(2,2-dimethylpropylidene)

diphenylmethanamine (251 mg, 1.0 mmol, 1.0 equiv). The product was subjected to purification by flash column

chromatography (9:1, hexanes:Et2O) to afford (R)-2-(benzhydrylamino)-3,3-dimethylbutanenitrile (275 mg, 0.99

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mmol, 99% yield) as a clear colorless oil. The enantiomeric excess was determined to be 93% by chiral HPLC
24
analysis (AS-H, 5.0% IPA in hexanes, 1.0 mL/min, 210 nm, tR(major)= 8.7 min, tR(minor) = 6.0 min); [α]D =
20
+113.0° (c = 1.0, CHCl3); lit39 [α]D = +87.1° (c = 1.19, CHCl3), 63% ee, (R)-enantiomer. Spectroscopic data match

previously reported data.33

(R)-2-(benzhydrylamino)-3-ethyl-3-methylpentanenitrile (3b):

The reaction was run at –30 °C for 20 h without stirring using (E)-N-(2-ethyl-2-

methylbutylidene)diphenylmethanamine (279 mg, 1.0 mmol, 1.0 equiv). The product was subjected to purification

by flash column chromatography (9:1, hexanes:Et2O) to afford (R)-2-(benzhydrylamino)-3-ethyl-3-

methylpentanenitrile (303 mg, 0.99 mmol, 99% yield) as a clear colorless oil. The enantiomeric excess was

determined to be 96% by chiral HPLC analysis (AS-H, 5.0% IPA in hexanes, 1.0 mL/min, 210 nm, tR(major)= 8.4
23
min, tR(minor) = 5.3 min); [α]D = +124.6° (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.48 (2H, d, J = 7.0

Hz), 7.45 (2H, d, J = 7.0 Hz), 7.32 (4H, td, J = 8.0, 3.0 Hz), 7.22-7.27 (2H, m), 5.11 (1H, s), 3.21 (1H, d, J = 13.5

Hz), 1.80 (1H, d, J = 13.0 Hz), 1.54 (3H, apparent sextet, J = 7.4 Hz), 1.41 (1H, apparent sextet, J = 7.3 Hz), 0.98

(3H, s), 0.75 (6H, apparent td, J = 7.5, 2.2 Hz). 13C{1H} NMR (125 MHz, CDCl3): δ 143.5, 141.3, 128.7, 128.7,

127.8, 127.7, 127.5, 126.9, 119.7, 65.7, 56.1, 39.3, 28.2, 27.4, 20.5, 7.80, 7.59. IR (cm-1): 3314 (w), 3028 (w), 2967

(m), 2939 (m), 2224 (w), 1493 (m), 1453 (m), 1112 (m), 745 (s), 702 (s).

(R)-2-(benzhydrylamino)-3-methyl-3-phenylbutanenitrile (3c):

39
Wunnemann, S., Frohlich, R. & Hoppe, D. Asymmetric Strecker reaction of N-benzlhydrylimines utilising new
tropos biphenyldiol-based ligands. Eur. J. Org. Chem. 684–692 (2008).

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The reaction was run at –30 °C for 20 h without stirring using (E)-N-(2-methyl-2-

phenylpropylidene)diphenylmethanamine (313 mg, 1.0 mmol, 1.0 equiv). The product was subjected to purification

by flash column chromatography (9:1, hexanes:Et2O) to afford (R)-2-(benzhydrylamino)-3-methyl-3-

phenylbutanenitrile (331 mg, 0.97 mmol, 97% yield) as a white solid. The enantiomeric excess was determined to

be 85% by chiral HPLC analysis (OD-H, 1.0% IPA in hexanes, 1.0 mL/min, 220 nm, tR(major)= 7.8 min, tR(minor)
24
= 9.0 min); [α]D = +81.8° (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.45-7.47 (2H, m), 7.37-7.43 (4H, m),

7.28-7.35 (8H, m), 7.24-7.26 (1H, m), 5.06 (1H, s), 3.47 (1H, d, J = 12.5 Hz), 1.72 (1H, d, J = 12.5 Hz), 1.68 (6H,

s). 13C{1H} NMR (125 MHz, CDCl3): δ 143.4, 143.3, 141.1, 128.7, 128.6, 128.4, 127.6, 127.4, 127.0, 126.8, 126.5,

119.2, 65.3, 59.2, 40.8, 25.9, 25.0. IR (cm-1): 3348 (w), 3058 (w), 3025 (w), 2975 (w), 2228 (w), 1493 (m), 1452

(m), 1309 (m), 1122 (m), 1032 (m), 889 (w), 768 (s), 745 (s), 702 (s).

(R)-2-(benzhydrylamino)-2-(1-methylcyclohexyl)acetonitrile (3d):

The reaction was run at –30 °C for 20 h without stirring using (E)-N-((1-

methylcyclohexyl)methylene)diphenylmethanamine (291 mg, 1.0 mmol, 1.0 equiv). The product subjected to

purification by flash column chromatography (9:1, hexanes:Et2O) to afford (R)-2-(benzhydrylamino)-2-(1-

methylcyclohexyl)acetonitrile (315 mg, 0.99 mmol, 99% yield) as a clear colorless oil. The enantiomeric excess

was determined to be 95% by chiral HPLC analysis (AD-H, 5.0% IPA in hexanes, 1.0 mL/min, 230 nm, tR(major)=
24
5.8 min, tR(minor) = 5.2 min); [α]D = +108.8° (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.50 (2H, d, J =

7.0 Hz), 7.45 (2H, d, J = 7.0 Hz), 7.30-7.35 (4H, m), 7.23-7.28 (2H, m), 5.12 (1H, s), 3.23 (1H, d, J = 12.5 Hz), 1.80

(1H, d, J = 13.0 Hz), 1.48-1.55 (5H, m), 1.39-1.45 (6H, m), 1.22-1.26 (1H, m), 1.09 (3H, s). 13C{1H} NMR (125

MHz, CDCl3): δ 143.5, 141.4, 128.7, 127.7, 127.6, 127.0, 119.4, 65.7, 58.3, 40.3, 36.8, 34.8, 34.2, 25.9, 21.6, 21.4,

20.6. IR (cm-1): 3314 (w), 3028 (w), 2927 (m), 2853 (m), 2224 (w), 1493 (w), 1452 (m), 1104 (m), 1028 (m), 745

(s), 701 (s).

(R)-2-(benzhydrylamino)-2-(1-adamantyl)acetonitrile (3e):

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The reaction was run at –30 °C for 20 h without stirring using (E)-N-(1-adamantyl)diphenylmethanamine (330 mg,

1.0 mmol, 1.0 equiv). The product was subjected to purification by flash column chromatography (9:1,

hexanes:Et2O) to afford (R)-2-(benzhydrylamino)-2-(1-adamantyl)acetonitrile (352 mg, 0.99 mmol, 99% yield) as

an off-white solid. The enantiomeric excess was determined to be 93% by chiral HPLC analysis (OD-H, 2.0% IPA
24
in hexanes, 1.0 mL/min, 220 nm, tR(major)= 5.4 min, tR(minor) = 5.7 min); [α]D = +69.9° (c = 1.0, CHCl3); 1H

NMR (500 MHz, CDCl3): δ 7.51 (2H, d, J = 7.5 Hz), 7.47 (2H, d, J = 7.0 Hz), 7.32-7.39 (4H, m), 7.24-7.29 (2H, m),
13
5.14 (1H, s), 3.03 (1H, s), 2.08 (3H, s), 1.63-1.86 (13H, m). C{1H} NMR (125 MHz, CDCl3): δ 143.5, 141.3,

128.7, 128.7, 127.6, 127.5, 127.4, 127.0, 119.0, 65.5, 59.5, 38.7, 37.3, 36.6, 36.5, 35.8, 28.1. IR (cm-1): 3302 (w),

3025 (w), 2912 (m), 2849 (m), 2222 (w), 1493 (w), 1450 (m), 1346 (w), 1029 (w), 895 (w), 743 (s), 700 (s).

(R)-2-(benzhydrylamino)-2-cyclohexylacetonitrile (3f):

The reaction was run at –30 °C for 20 h without stirring using (E)-N-(cyclohexylmethylene)diphenylmethanamine

(277 mg, 1.0 mmol, 1.0 equiv). The product was subjected to purification by flash column chromatography (9:1,

hexanes:Et2O) to afford (R)-2-(benzhydrylamino)-2-cyclohexylacetonitrile (301 mg, 0.99 mmol, 99% yield) as a

white solid. The enantiomeric excess was determined to be 74% by chiral HPLC analysis (OD-H, 2.0% IPA in
23
hexanes, 1.0 mL/min, 230 nm, tR(major)= 6.3 min, tR(minor) = 8.0 min); [α]D = +59.9° (c = 1.0, CHCl3). 1H NMR

(500 MHz, CDCl3): δ 7.50 (2H, d, J = 7.0 Hz), 7.44 (2H, d, J = 7.0 Hz), 7.31-7.37 (4H, m), 7.23-7.29 (2H, m), 5.15

(1H, s), 3.25 (1H, d, J = 7.0 Hz), 2.00 (1H, d, J = 12.5 Hz), 1.87 (1H, d, J = 10.5 Hz), 1.79-1.82 (2H, m), 1.69-1.75

(2H, m), 1.11-1.33 (6H, m). 13C{1H} NMR (125 MHz, CDCl3): δ 143.3, 141.3, 128.8, 128.7, 127.6, 127.5, 127.3,

127.0, 119.6, 65.5, 54.1, 40.9, 29.6, 29.0, 26.0, 25.7, 25.6. IR (cm-1) 3329 (w), 3028 (w), 2930 (m), 2845 (m), 2222

(w), 1493 (m), 1450 (m), 1112 (m), 1027 (m), 880 (m), 750 (s), 707 (s), 697 (s).

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(R)-2-(benzhydrylamino)-2-(4-methoxyphenyl)acetonitrile (3g):

The reaction was run at –30 °C for 20 h without stirring using (E)-N-(4-methoxybenzylidene)diphenylmethanamine

(301mg, 1.0 mmol, 1.0 equiv). The product was subjected to purification by flash column chromatography (7:1,

hexanes:Et2O) to afford (R)-2-(benzhydrylamino)-2-(4-methoxyphenyl)acetonitrile (324 mg, 0.99 mmol, 99% yield)

as a white solid. The enantiomeric excess was determined to be 99% by chiral HPLC analysis (S,S-whelk, 2.0%
24
IPA in hexanes, 1.0 mL/min, 200 nm, tR(major)= 19.6 min, tR(minor) = 18.4 min); [α]D = +43.0° (c = 1.0, CHCl3);
24
lit40 [α]D = –38.0° (c = 1.0, CHCl3), 91% ee, (S)-enantiomer. Spectroscopic data match previously reported data.33

(R)-2-(benzhydrylamino)-2-p-tolylacetonitrile (3h):

The reaction was run at –30 °C for 20 h without stirring using (E)-N-(4-methylbenzylidene)diphenylmethanamine

(285 mg, 1.0 mmol, 1.0 equiv). The product was subjected to purification by flash column chromatography (9:1,

hexanes:Et2O) to afford (R)-2-(benzhydrylamino)-2-p-tolylacetonitrile (307 mg, 0.98 mmol, 98% yield) as a white

solid. The enantiomeric excess was determined to be 98% by chiral HPLC analysis (OD-H, 5.0% IPA in hexanes,
24 20
1.0 mL/min, 220 nm, tR(major)= 6.7 min, tR(minor) = 7.3 min); [α]D = +52.8° (c = 1.0, CHCl3); lit39 [α]D =

+41.0° (c = 1.13, CHCl3), 80% ee, (R)-enantiomer. Spectroscopic data matched previously reported data.41

(R)-2-(benzhydrylamino)-2-phenylacetonitrile (3i):

40
Banphavichit, V., Mansawat, W., Bhanthumnavin, W. & Vilaivan, T. A highly enantioselective Strecker reaction
catalyzed by titanium-N-salicyl-beta-aminoalcohol complexes. Tetrahedron 60, 10559–10568 (2004).
41
Jiao, Z., Feng, X., Liu, B., Chen, F., Zhang, G. & Jiang, Y. Enantioselective Strecker reactions between aldimines
and trimethylsilyl cyanide promoted by chiral N,N '-dioxides. Eur. J. Org. Chem. 3818–3826 (2003).

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The reaction was run at –30 °C for 20 h without stirring using (E)-N-benzylidenediphenylmethanamine (271 mg, 1.0

mmol, 1.0 equiv). The product was subjected to purification by flash column chromatography (9:1, hexanes:Et2O)

to afford (R)-2-(benzhydrylamino)-2-phenylacetonitrile (293 mg, 0.98 mmol, 98% yield) as a white solid. The

enantiomeric excess was determined to be 98% by chiral HPLC analysis (OD-H, 5.0% IPA in hexanes, 1.0 mL/min,
24 24
220 nm, tR(major)= 7.1 min, tR(minor) = 7.9 min); [α]D = +66.1° (c = 1.0, CHCl3); lit33 [α]D = –64.2° (c = 5.0,

CHCl3), >99% ee, (S)-enantiomer. Spectroscopic data match previously reported data.33

(R)-2-(benzhydrylamino)-2-(4-chlorophenyl)acetonitrile (3j):

The reaction was run at –30 °C for 20 h without stirring using (E)-N-(4-chlorobenzylidene)diphenylmethanamine

(306 mg, 1.0 mmol, 1.0 equiv). The product was subjected to purification by flash column chromatography (9:1,

hexanes:Et2O) to afford (R)-2-(benzhydrylamino)-2-(4-chlorophenyl)acetonitrile (324 mg, 0.97 mmol, 97% yield) as

a white solid. The enantiomeric excess was determined to be 98% ee by chiral HPLC analysis (OD-H, 5.0% IPA in
24
hexanes, 1.0 mL/min, 220 nm, tR(major)= 9.6 min, tR(minor) = 11.7 min); [α]D = +42.3° (c = 1.0, CHCl3); lit39
20
[α]D = +35.1° (c = 1.09, CHCl3), 84% ee, (R)-enantiomer. Spectroscopic data match previously reported data.42

(R)-2-(benzhydrylamino)-2-(4-(trifluoromethyl)phenyl)acetonitrile (3k):

42
Iyer, M. S., Gigstad, K. M., Namdev, N. D. & Lipton, M. Asymmetric catalysis of the Strecker amino acid
synthesis by a cyclic dipeptide. J. Am. Chem. Soc. 118, 4910–4911 (1996).

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The reaction was run at 0 °C for 20 h with stirring using (E)-diphenyl-N-(4-

(trifluoromethyl)benzylidene)methanamine (339 mg, 1.0 mmol, 1.0 equiv). The product was subjected to

purification by flash column chromatography (9:1, hexanes:Et2O) to afford (R)-2-(benzhydrylamino)-2-(4-

(trifluoromethyl)phenyl)acetonitrile (360 mg, 0.98 mmol, 98% yield) as a white solid. This enantiomeric excess was

determined to be 96% by chiral HPLC analysis (OD-H, 5.0% IPA in hexanes, 1.0 mL/min, 220 nm, tR(major)= 11.5
24
min, tR(minor) = 13.3 min); [α]D = +50.3° (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.72 (4H, s), 7.61 (2H,

d, J = 8.0 Hz), 7.49 (2H, d, J = 7.5 Hz), 7.42 (2H, t, J = 7.8 Hz), 7.31-7.36 (3H, m), 7.25-7.28 (1H, m), 5.29 (1H, s),

4.69 (1H, d, J = 9.0 Hz), 2.23 (1H, d, J = 8.5 Hz). 13C{1H} NMR (125 MHz, CDCl3): δ 142.4, 140.7, 138.7, 131.3

(q, JC-F = 32.3 Hz), 129.1, 128.8, 128.1, 127.8, 127.7, 127.4, 127.0, 125.9 (q, JC-F = 2.5 Hz), 123.7 (q, JC-F = 270.0

Hz), 118.1, 65.6, 51.9. IR (cm-1): 3297 (m), 3065 (w), 3028 (w), 2842 (w), 2231 (w), 1618 (w), 1453 (m), 1323 (s),

1166 (m), 1125 (s), 1111 (s), 1066 (m), 1017 (m), 922 (m), 749 (m), 699 (s).

(R)-4-((benzhydrylamino)(cyano)methyl)benzonitrile (3l):

The reaction was run at 0 °C for 20 h with stirring using (E)-4-((benzhydrylimino)methyl)benzonitrile (296 mg, 1.0

mmol, 1.0 equiv) and 10 mol% of (S)-N-benzhydryl-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N,3,3-

trimethyl butanamide (4e). The product was subjected to purification by flash column chromatography (9:1,

hexanes:Et2O) to afford (R)-4-((benzhydrylamino) (cyano)methyl)benzonitrile (310 mg, 0.96 mmol, 96% yield) as a

white solid. The enantiomeric excess was determined to be 93% by chiral HPLC analysis (OD-H, 5.0% IPA in
24
hexanes, 1.0 mL/min, 230 nm, tR(major)= 41.1 min, tR(minor) = 56.4 min); [α]D = +27.3° (c = 1.0, CHCl3). 1H

NMR (500 MHz, CDCl3): δ 7.72 (4H, s), 7.57 (2H, d, J = 7.5 Hz), 7.45 (2H, d, J = 7.5 Hz), 7.39 (2H, t, J = 7.8 Hz),
13
7.29-7.34 (3H, m), 7.23-7.27 (1H, m), 5.25 (1H, s), 4.67 (1H, br s), 2.25 (1H, br s). C{1H} NMR (125 MHz,

CDCl3): δ 142.2, 140.5, 139.7, 132.7, 129.1, 128.8, 128.2, 128.0, 127.9, 127.4, 127.0, 118.1, 117.7, 113.1, 65.7,

52.0. IR (cm-1): 3310 (m), 3296 (m), 3025 (w), 2925 (w), 2845 (w), 2232 (m), 1609 (w), 1492 (m), 1453 (m), 1349

(m), 1189 (m), 925 (m), 746 (s), 703 (s).

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(R)-2-(benzhydrylamino)-2-(4-bromophenyl)acetonitrile (3m):

The reaction was run at –30 °C for 20 h with stirring using (E)-N-(4-bromobenzylidene)diphenylmethanamine (350

mg, 1.0 mmol, 1.0 equiv). The product was subjected to purification by flash column chromatography (9:1,

hexanes:Et2O) to afford (R)-2-(benzhydrylamino)-2-(4-bromophenyl)acetonitrile (369 mg, 0.98 mmol, 98% yield) as

a white solid. The enantiomeric excess was determined to be 99% by chiral HPLC analysis (OD-H, 2.0% IPA in
24
hexanes, 1.0 mL/min, 220 nm, tR(major)= 15.1 min, tR(minor) = 18.4 min); [α]D = +29.4° (c = 1.0, CHCl3). 1H

NMR (500 MHz, CDCl3): δ 7.56-7.59 (4H, m), 7.46 (4H, t, J = 8.8 Hz), 7.41 (2H, t, J = 7.5 Hz), 7.30-7.35 (3H, m),

7.26 (1H, t, J = 7.3 Hz), 5.26 (1H, s), 4.58 (1H, d, J = 11.5 Hz), 2.18 (1H, d, J = 12.0 Hz). 13C{1H} NMR (125 MHz,

CDCl3): δ 142.4, 140.8, 133.8, 132.1, 129.0, 128.8, 128.7, 128.0, 127.7, 127.3, 127.0, 123.1, 118.2, 65.5, 51.7. IR

(cm-1): 3303 (m), 3062 (w), 3026 (w), 2836 (w), 2224 (w), 1594 (w), 1488 (m), 1453 (m), 1187 (w), 1100 (m), 920

(m), 819 (m), 745 (s), 698 (s).

(R)-2-(benzhydrylamino)-2-(2-methoxyphenyl)acetonitrile (3n):

The reaction was run at –30 °C for 20 h without stirring using (E)-N-(2-methoxybenzylidene)diphenylmethanamine

(301 mg, 1.0 mmol, 1.0 equiv). The product was subjected to purification by flash column chromatography (7:1,

hexanes:Et2O) to afford (R)-2-(benzhydrylamino)-2-(2-methoxyphenyl)acetonitrile (318 mg, 0.97 mmol, 97% yield)

as a white solid. The enantiomeric excess was determined to be 88% by chiral HPLC analysis (OD-H, 2.0% IPA in
23
hexanes, 1.0 mL/min, 220 nm, tR(major)= 11.7 min, tR(minor) = 12.8 min); [α]D = +65.3° (c = 1.0, CHCl3); lit40
24
[α]D = –57.0° (c = 1.0, CHCl3), 83% ee, (S)-enantiomer. 1H NMR (500 MHz, CDCl3): δ 7.56 (2H, d, J = 8.0 Hz),

7.48 (2H, d, J = 8.0 Hz), 7.37-7.41 (3H, m), 7.30-7.35 (4H, m), 7.24-7.28 (1H, m), 7.00 (1H, t, J = 7.5 Hz), 6.97

(1H, d, J = 8.5 Hz), 5.23 (1H, s), 4.71 (1H, br d, J = 6.5 Hz), 3.89 (3H, s), 2.60 (1H br s). 13C{1H} NMR (125 MHz,

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CDCl3): δ 157.0, 142.9, 141.4, 130.5, 128.8, 128.7, 128.7, 127.6, 127.5, 127.4, 127.2, 126.4, 120.9, 119.0, 111.3,

65.3, 55.5, 48.4. IR (cm-1): 3322 (w), 3027 (w), 2975 (w), 2939 (w), 2227 (w), 1600 (m), 1493 (m), 1450 (m), 1248

(m), 1026 (m), 910 (m), 747 (s), 698 (s).

(R)-2-(benzhydrylamino)-2-(2-bromophenyl)acetonitrile (3o):

The reaction was run at 0 °C for 20 h with stirring using (E)-N-(2-bromobenzylidene)diphenylmethanamine (350

mg, 1.0 mmol, 1.0 equiv). The product was subjected to purification by flash column chromatography (9:1,

hexanes:Et2O) to afford (R)-2-(benzhydrylamino)-2-(2-bromophenyl)acetonitrile (362 mg, 0.96 mmol, 96% yield) as

a white solid. This enantiomeric excess was determined to be 97% by chiral HPLC analysis (OD-H, 2.0% IPA in
25
hexanes, 1.0 mL/min, 200 nm, tR(major)= 12.7 min, tR(minor) = 17.8 min); [α]D = +130.0° (c = 1.0, CHCl3);
24
lit33[α]D = –122° (c = 5.0, CHCl3), >99% ee, (S)-enantiomer. Spectroscopic data match previously reported data.33

(R)-2-(benzhydrylamino)-2-(3-bromophenyl)acetonitrile (3p):

The reaction was run at 0 °C for 20 h with stirring using (E)-N-(3-bromobenzylidene)diphenylmethanamine (350

mg, 1.0 mmol, 1.0 equiv). The product was subjected to purification by flash column chromatography (9:1,

hexanes:Et2O) to afford (R)-2-(benzhydrylamino)-2-(3-bromophenyl)acetonitrile (365 mg, 0.97 mmol, 97% yield) as

a white solid. The enantiomeric excess was determined to be 92% by chiral HPLC analysis (OD-H, 2.0% IPA in
24
hexanes, 1.0 mL/min, 220 nm, tR(major)= 13.0 min, tR(minor) = 14.6 min); [α]D = +37.5° (c = 1.0, CHCl3). 1H

NMR (500 MHz, CDCl3): δ 7.74 (1H, s), 7.59 (2H, t, J = 7.5 Hz), 7.50-7.54 (2H, m), 7.47 (2H, d, J = 7.5 Hz), 7.41

(2H, t, J = 7.5 Hz), 7.30-7.35 (4H, m), 7.25-7.28 (1H, m), 5.26 (1H, s), 4.60 (1H, d, J = 12.0 Hz), 2.19 (1H, d, J =

11.5 Hz). 13C{1H} NMR (125 MHz, CDCl3): δ 142.4, 140.7, 136.9, 132.2, 130.4, 130.3, 129.0, 128.8, 128.0, 127.7,

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127.4, 127.0, 125.8, 122.9, 118.1, 65.6, 51.7. IR (cm-1): 3314 (m), 3021 (w), 2962 (w), 2852 (w), 2230 (w), 1570

(m), 1493 (m), 1451 (m), 1423 (m), 1072 (m), 880 (m), 787 (s), 753 (s), 700 (s), 680 (s).

(S)-2-(benzhydrylamino)-2-(furan-2-yl)acetonitrile (3q):

The reaction was run at –30 °C for 20 h without stirring using (E)-N-(furan-2-ylmethylene)diphenylmethanamine

(261 mg, 1.0 mmol, 1.0 equiv). The product was subjected to purification by flash column chromatography (9:1,

hexanes:Et2O) to afford (S)-2-(benzhydrylamino)-2-(furan-2-yl)acetonitrile (285 mg, 0.99 mmol, 99% yield) as a

white solid. The enantiomeric excess was determined to be 93% by chiral HPLC analysis (OD-H, 2.0% IPA in
24
hexanes, 1.0 mL/min, 220 nm, tR(major)= 11.2 min, tR(minor) = 13.4 min); [α]D = +32.9° (c = 1.0, CHCl3); lit40
21
[α]D = –25.0° (c = 1.0, CHCl3), 91% ee, (R)-enantiomer. Spectroscopic data match previously reported data.40

(R)-2-(benzhydrylamino)-2-(furan-3-yl)acetonitrile (3r):

The reaction was run at –30 °C for 20 h without stirring using (E)-N-(furan-3-ylmethylene)diphenylmethanamine

(261 mg, 1.0 mmol, 1.0 equiv). The product was subjected to purification by flash column chromatography (9:1,

hexanes:Et2O) to afford (R)-2-(benzhydrylamino)-2-(furan-3-yl)acetonitrile (282 mg, 0.98 mmol, 98% yield) as a

white solid. This enantiomeric excess was determined to be 97% by chiral HPLC analysis (OD-H, 2.0% IPA in
24
hexanes, 1.0 mL/min, 220 nm, tR(major)= 11.9 min, tR(minor) = 12.7 min); [α]D = +64.6° (c = 1.0, CHCl3). 1H

NMR (500 MHz, CDCl3): δ 7.61 (1H, s), 7.53 (2H, d, J = 10.0 Hz), 7.44 (3H, d, J = 9.5 Hz), 7.22-7.38 (6H, m),

6.54 (1H, s), 5.21 (1H, s), 4.51 (1H, d, J = 15.0 Hz), 2.12 (1H, d, J = 15.0 Hz). 13C{1H} NMR (125 MHz, CDCl3): δ

144.0, 142.6, 140.9, 140.4, 129.0, 128.8, 128.0, 127.7, 127.3, 127.0, 120.9, 118.4, 109.2, 65.3, 44.6. IR (cm-1): 3295

(m), 3135 (w), 3061 (w), 2842 (w), 2231 (w), 1596 (w), 1492 (m), 1474 (m), 1451 (m), 1162 (m), 1102 (m), 1025

(m), 902 (m), 874 (), 807 (m), 744 (s), 699 (s).

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(S)-2-(benzhydrylamino)-2-(thiophen-2-yl)acetonitrile (3s):

The reaction was run at 0 °C for 20 h with stirring using (E)-diphenyl-N-(thiophen-2-ylmethylene)methanamine

(277 mg, 1.0 mmol, 1.0 equiv). The product was subjected to purification by flash column chromatography (9:1,

hexanes:Et2O) to afford (S)-2-(benzhydrylamino)-2-(thiophen-2-yl)acetonitrile (294 mg, 0.97 mmol, 97% yield) as a

white solid. The enantiomeric excess determined to be 95% by chiral HPLC analysis (OD-H, 2.0% IPA in hexanes,
24 24
1.0 mL/min, 220 nm, tR(major)= 10.0 min, tR(minor) = 11.1 min); [α]D = +68.6° (c = 1.0, CHCl3); lit40 [α]D =

76.0° (c = 1.0, CHCl3), 98% ee, (S)-enantiomer. 1H NMR (500 MHz, CDCl3): δ 7.59 (2H, d, J = 8.0 Hz), 7.48 (2H,

d, J = 8.0 Hz), 7.25-7.41 (8H, m), 7.01-7.02 (1H, m), 5.25 (1H, s), 4.79 (1H, d, J = 12.0 Hz), 2.40 (1H, d, J = 12.0
13
Hz). C{1H} NMR (125 MHz, CDCl3): δ 142.4, 140.7, 138.2, 129.0, 128.8, 128.0, 127.7, 127.2, 127.0, 126.8,

126.6, 126.0, 118.1, 65.3, 48.1. IR (cm-1): 3295 (m), 3104 (w), 3083 (w), 3059 (w), 3023 (w), 2842 (w), 2230 (w),

1491 (m), 1474 (m), 1451 (m), 1188 (m), 1095 (m), 1025 (m), 915 (m), 843 (m), 744 (m), 725 (m), 698 (s).

(R)-2-(benzhydrylamino)-2-cyclohexenylacetonitrile (3t):

The reaction was run at –30 °C for 20 h without stirring using (E)-N-(cyclohexenylmethylene)diphenylmethanamine

(263 mg, 1.0 mmol, 1.0 equiv). The product was purified by flash column chromatography (9:1, hexanes:Et2O) to

afford (R)-2-(benzhydrylamino)-2-cyclohexenylacetonitrile (298 mg, 0.99 mmol, 99% yield) as a clear colorless oil.

The enantiomeric excess was determined to be 95% ee by chiral HPLC analysis (AD-H, 3.0% IPA in hexanes, 1.0
23 1
mL/min, 210 nm, tR(major)= 11.2 min, tR(minor) = 20.2 min); [α]D = +65.4° (c = 1.0, CHCl3). H NMR (500

MHz, CDCl3): δ 7.53 (2H, d, J = 7.0 Hz), 7.46 (2H, d, J = 7.5 Hz), 7.32-7.40 (4H, m), 7.24-7.30 (2H, m), 6.06 (1H,

d, J = 1.5 Hz), 5.17 (1H, s), 3.89 (1H, d, J = 8.0 Hz), 2.37-2.41 (1H, m), 2.08-2.12 (2H, m), 1.97-2.01 (1H, m), 1.86
13
(1H, d, J = 9.5 Hz), 1.71 (2H, p, J = 6.0 Hz), 1.62 (2H, apparent sextet, J = 5.7 Hz). C{1H} NMR (125 MHz,

CDCl3): δ 143.0, 141.3, 131.9, 128.8, 128.0, 128.3, 127.6, 127.5, 127.4, 127.1, 126.8, 118.6, 65.2, 54.2, 25.9, 24.9,

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22.4, 21.8. IR (cm-1): 3313 (w), 3062 (w), 3029 (w), 2928 (m), 2858 (w), 2228 (w), 1493 (m), 1452 (m), 1076 (m),

1028 (m), 896 (m), 843 (m), 745 (s), 701 (s), 678 (s).

(R,E)-2-(benzhydrylamino)-3-methylhex-3-enenitrile (3u):

The reaction was run at –30 °C for 20 h without stirring using (E)-N-((E)-2-methylpent-2-

enylidene)diphenylmethanamine (263 mg, 1.0 mmol, 1.0 equiv). The product was subjected to purification by flash

column chromatography (9:1, hexanes:Et2O) to afford (R,E)-2-(benzhydrylamino)-3-methylhex-3-enenitrile (286

mg, 0.98 mmol, 98% yield) as a clear colorless oil. The enantiomeric excess was determined to be 91% ee by chiral
23
HPLC analysis (AD-H, 1.0% IPA in hexanes, 1.0 mL/min, 220 nm, tR(major)= 9.4 min, tR(minor) = 8.5 min); [α]D

= +66.9° (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.50-7.52 (2H, m), 7.44-7.45 (2H, m), 7.23-7.37 (6H,

m), 5.74 (1H, dt, J = 1.0, 6.5 Hz), 5.13 (1H, s), 3.88 (1H, s), 2.08-2.11 (2H, m), 1.86-1.90 (1H, m), 1.80 (3H, s),
13
0.98-1.02 (3H, m). C{1H} NMR (125 MHz, CDCl3): δ 142.9, 141.4, 132.0, 128.8, 128.7, 128.4, 127.7, 127.5,

127.4, 127.1, 118.7, 65.2, 55.2, 21.2, 13.9, 13.6. IR (cm-1): 3313 (w), 3062 (w), 3028 (w), 2965 (w), 2932 (w), 2873

(w), 2228 (w), 1493 (m), 1453 (m), 1306 (w), 1189 (w), 1080 (w), 911 (w), 864 (w), 745 (s), 699 (s).

(R,E)-2-(benzhydrylamino)-4-phenylbut-3-enenitrile (3v):

The reaction was run at –30 °C for 20 h with stirring (the reaction mixture was heterogenous) using (E)-diphenyl-N-

((E)-3-phenylallylidene)methanamine (297 mg, 1.0 mmol, 1.0 equiv). The product was subjected to purification by

flash column chromatography (9:1, hexanes:Et2O) to afford (R,E)-2-(benzhydrylamino)-4-phenylbut-3-enenitrile

(323 mg, 0.99 mmol, 99% yield) as a white solid. The enantiomeric excess was determined to be 95% ee by chiral

HPLC analysis (AD-H, 3.0% IPA in hexanes, 1.0 mL/min, 210 nm, tR(major)= 13.2 min, tR(minor) = 19.9 min);
23
[α]D = +13.8° (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.56 (2H, d, J = 8.0 Hz), 7.49 (2H, d, J = 7.5 Hz),

7.26-7.44 (11H, m), 6.94 (1H, d, J = 16.5 Hz), 6.25 (1H, dd, J = 5.0, 16.0 Hz), 5.25 (1H, s), 4.26 (1H, br s), 2.03

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(1H, br s). 13C{1H} NMR (125 MHz, CDCl3): δ 143.1, 141.3, 135.6, 134.1, 129.3, 129.1, 129.0, 128.9, 128.2, 128.0,

127.7, 127.4, 127.1, 122.7, 118.6, 65.6, 50.4. IR (cm-1): 3304 (m), 3056 (w), 3027 (w), 2235 (w), 1492 (m), 1452

(m), 1312 (w), 1108 (m), 963 (m), 743 (s), 702 (s), 695 (s).

(R,E)-2-(benzhydrylamino)hept-3-enenitrile (3w):

The reaction was run at –30 °C for 20 h using (E)-N-((E)-hex-2-enylidene) diphenylmethanamine (263 mg, 1.0

mmol, 1.0 equiv). The product was subjected to purification by flash column chromatography (9:1, hexanes:Et2O)

to afford (R,E)-2-(benzhydrylamino)hept-3-enenitrile (281 mg, 0.97 mmol, 97% yield, ~95% purity) as a clear

colorless oil. The enantiomeric excess was determined to be 73% by chiral HPLC analysis (OD-H, 2.0% IPA in
23 1
hexanes, 1.0 mL/min, 220 nm, tR(major)= 7.9 min, tR(minor) = 12.2 min); [α]D = +36.2° (c = 1.0, CHCl3). H

NMR (500 MHz, CDCl3): δ 7.49 (2H, d, J = 6.8 Hz), 7.43 (2H, d, J = 7.2 Hz), 7.20-7.36 (6H, m), 5.99-6.07 (1H, m),

5.51-5.57 (1H, m), 5.16 (1H, s), 4.00-4.04 (1H, m), 2.07 (2H, q, J = 7.2 Hz), 1.85 (1H, d, J = 12.0 Hz), 1.43 (2H,
13
apparent sextet, J = 7.6 Hz), 0.92 (3H, t, J = 7.4 Hz). C{1H} NMR (125 MHz, CDCl3): δ 142.9, 141.2, 135.7,

128.9, 128.7, 127.7, 127.6, 127.4, 127.1, 123.4, 118.6, 65.3, 49.9, 34.0, 21.9, 13.6. IR (cm-1): 3314 (w), 3062 (w),

3028 (w), 2959 (w), 2930 (w), 2872 (w), 2228 (w), 1599 (w), 1493 (m), 1453 (m), 1305 (w), 1079 (w), 1028 (w),

967 (m), 744 (s), 698 (s).

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HPLC chromatograms of racemic and enantiomerically enriched α-aminonitriles

(R)-2-(benzhydrylamino)-3,3-dimethylbutanenitrile (3a):

Racemic (AS-H, 5.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (93% ee)

(R)-2-(benzhydrylamino)-3-ethyl-3-methylpentanenitrile (3b):

Racemic (AS-H, 5.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (96% ee)

(R)-2-(benzhydrylamino)-3-methyl-3-phenylbutanenitrile (3c):

Racemic (OD-H, 1.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (85% ee)

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(R)-2-(benzhydrylamino)-2-(1-methylcyclohexyl)acetonitrile (3d):

Racemic (AD-H, 5.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (95% ee)

(R)-2-(benzhydrylamino)-2-(1-adamantyl)acetonitrile (3e):

Racemic (OD-H, 2.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (93% ee)

(R)-2-(benzhydrylamino)-2-cyclohexylacetonitrile (3f):

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Racemic (OD-H, 2.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (74% ee)

(R)-2-(benzhydrylamino)-2-(4-methoxyphenyl)acetonitrile (3g):

Racemic (S,S-whelk, 2.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (99% ee)

(R)-2-(benzhydrylamino)-2-p-tolylacetonitrile (3h):

Racemic (OD-H, 5.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (98% ee)

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(R)-2-(benzhydrylamino)-2-phenylacetonitrile (3i):

Racemic (OD-H, 5.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (98% ee)

R)-2-(benzhydrylamino)-2-(4-chlorophenyl)acetonitrile (3j):

Racemic (OD-H, 5.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (98% ee)

(R)-2-(benzhydrylamino)-2-(4-(trifluoromethyl)phenyl)acetonitrile (3k):

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Racemic (OD-H, 5.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (96% ee)

(R)-4-((benzhydrylamino)(cyano)methyl)benzonitrile (3l):

Racemic (OD-H, 5.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (93% ee)

(R)-2-(benzhydrylamino)-2-(4-bromophenyl)acetonitrile (3m):

Racemic (OD-H, 2.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (99% ee)

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(R)-2-(benzhydrylamino)-2-(2-methoxyphenyl)acetonitrile (3n):

Racemic (OD-H, 2.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (88% ee)

(R)-2-(benzhydrylamino)-2-(2-bromophenyl)acetonitrile (3o):

Racemic (OD-H, 2.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (97% ee)

(R)-2-(benzhydrylamino)-2-(3-bromophenyl)acetonitrile (3p):

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Racemic (OD-H, 2.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (92% ee)

(S)-2-(benzhydrylamino)-2-(furan-2-yl)acetonitrile (3q):

Racemic (OD-H, 2.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (93% ee)

(R)-2-(benzhydrylamino)-2-(furan-3-yl)acetonitrile (3r):

Racemic (OD-H, 2.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (97% ee)

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(S)-2-(benzhydrylamino)-2-(thiophen-2-yl)acetonitrile (3s):

Racemic (OD-H, 2.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (95% ee)

(R)-2-(benzhydrylamino)-2-cyclohexenylacetonitrile (3t):

Racemic (AD-H, 3.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (95% ee)

(R,E)-2-(benzhydrylamino)-3-methylhex-3-enenitrile (3u):

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Racemic (AD-H, 1.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (91% ee)

(R,E)-2-(benzhydrylamino)-4-phenylbut-3-enenitrile (3v):

Racemic (AD-H, 3.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (95% ee)

(R,E)-2-(benzhydrylamino)hept-3-enenitrile (3w):

Racemic (OD-H, 2.0% IPA in hexanes, 1.0 mL/min) Enantiomerically enriched (73% ee)

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Potassium cyanide-mediated synthesis of amino acids

(R)-Boc-tert-leucine

Method A: A 100-mL round-bottomed flask containing a stir bar was charged with Na2SO4 (8.0 g) and CH2Cl2 (40

mL). Trimethylacetaldehyde43 (7.65 mL, 52 mmol, 1.3 equiv) and aminodiphenylmethane44 (6.89 mL, 40 mmol, 1.0

equiv) were added sequentially via syringe while stirring. The flask was capped with a plastic stopper, and the

mixture was stirred at room temperature. The mixture became cloudy after 5 min. After stirring for 1 h, the solution

was decanted into a 200-mL round-bottomed flask, rinsing with CH2Cl2 (4 x 5 mL) and concentrated to 8–10 mL

using a rotary evaporator. The flask was then maintained at 1 torr for 10 min. A 5-cm diameter fritted disk funnel

was filled with a 2-cm high layer of silica gel. The funnel was rinsed with a solution of 20:1:0.5

hexanes/Et2O/triethylamine (50 mL) under reduced pressure, followed by a solution of 20:1 hexanes/Et2O (50 mL).

The oil prepared above was dissolved in 20:1 hexanes/Et2O (25 mL) and rinsed through the frit into a tared 250-mL

round-bottomed flask under reduced pressure, rinsing with 20:1 hexanes/Et2O (4 x 25 mL). The mixture was

concentrated (30 torr → 1 torr) to provide a clear, pale yellow oil that solidified into a white solid. The solid was

broken up into approximately 1-cm diameter pieces using a spatula, and was maintained at 1 torr for another 15 min

43
Technical grade trimethylaceteldehyde (~75%) purchased from Alfa Aesar was used. Identical results have been
obtained with reagent grade trimethylaceteldehyde on 10 mmol scale.
44
Aminodiphenylmethane was purchased from Aldrich and used as received.

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to provide N-(2,2-dimethyl propylidene)diphenylmethanamine as a white solid in approximately 98% 1H-NMR

purity. The product was used in the next step without further purification. Yield: 9.93 g (39.6 mmol, 99%).

Method B: A 100-mL round-bottomed flask containing a stir bar was charged with Na2SO4 (8.0 g) and CH2Cl2 (40

mL). Trimethylacetaldehyde43 (7.65 mL, 52 mmol, 1.3 equiv) and aminodiphenylmethane45 (6.89 mL, 40 mmol, 1.0

equiv) were added sequentially via syringe while stirring. The flask was capped with a plastic stopper, and the

mixture was stirred at room temperature. The mixture became cloudy after 5 min. After stirring for 1 h, the mixture

was decanted into a 200 mL round-bottomed flask, rinsing with CH2Cl2 (4 x 5 mL), and concentrated to 8–10 mL

using a rotary evaporator. The flask was then maintained at 1 torr for 10 min. The resulting pale yellow solid was

taken up in CH2Cl2 (50 mL), transferred to a 250-mL separatory funnel, and washed with NaHCO3 (50 mL). The

organic layer was dried over Na2SO4, filtered through a medium porosity fritted disk funnel into a 200-mL round-

bottomed flask, and concentrated in vacuo (30 torr → 1 torr) to provide a pale yellow oil that solidified to a white

solid within 5 min at 1 torr. The solid was broken up into approximately 1-cm diameter pieces using a spatula, and

was maintained at 1 torr for another 15 min to provide N-(2,2 dimethylpropylidene) diphenylmethanamine as a

white solid in approximately 98% 1H-NMR purity. The product was used in the next step without further

purification. Yield: 9.79 g (38.9 mmol, 97%).

This experiment was carried out as described in the Methods section.

The 100-mL round-bottomed flask containing (R)-2-(benzhydrylamino)-3,3-dimethylbutanenitrile was charged with

a 2-cm long stir bar. A solution of 40 mL of aqueous HCl/H2SO4 solution was generated as follows: a 50-mL

45
Aminodiphenylmethane used in Method B was distilled at 760 torr before use.

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Erlenmeyer flask was charged with deionized water (20 mL) and cooled in an ice bath for 5 min. Concentrated

hydrochloric acid (8 mL) was added over 1 min, followed by concentrated sulfuric acid (12 mL) over 5 min (in 2-

mL portions). The flask was swirled gently and was allowed to cool in the ice bath for 5 min. The solution was

then added to the flask containing the α-aminonitrile in one portion, and the flask was fitted with a chilled reflux

condenser. The flask was placed in an oil bath that was maintained at 120 °C, and reaction mixture was stirred for

44 h.

The reaction mixture was allowed to cool to room temperature and was then cooled for 2 min in an ice bath.46

Water (25 mL) and Et2O (25 mL) were carefully added over 2 min, and the entire contents of the flask were poured

into a 250-mL separatory funnel. The flask was rinsed with another 25-mL portion of diethyl ether and another 5-

mL portion of water, and the mixture was added to the separatory funnel. The organic and aqueous layers were

thoroughly mixed, and the aqueous layer was removed. The organic layer was further extracted with water (25 mL),

and the combined aqueous layers were cooled for 5 min in an ice bath within a 250-mL Erlenmeyer flask. Aqueous

NaOH (4 N) was added in 10–20-mL portions over 5 min with stirring until pH 11 was reached, as determined by

pH paper (approximately 120 mL total).47 The resulting mixture was transferred to a 500-mL separatory funnel and

washed with diethyl ether (2 x 50 mL). The aqueous layer was transferred to a 500-mL Erlenmeyer flask containing

a 4-cm long stirbar, acidified to pH 9.5–10.5 by addition of solid NaHCO3 (1 g), and cooled in an ice bath for 3 min

with stirring.

Dioxane (100 mL) was added, followed immediately by Boc2O (22 g, 100 mmol, 2.5 equiv) in one portion.48 The

flask was covered with Parafilm and allowed to warm to room temperature with stirring.49 The stir-rate was

adjusted to ensure thorough mixing of the upper organic layer and the lower aqueous layer, and the mixture was

46
The cooled reaction mixture is a biphasic oil with a dark brown-orange upper layer and a light orange lower layer.
47
A milky white precipitate formed after 100 mL of 4 N NaOH had been added.
48
The mixture became viscous upon addition of dioxane and partially solidified upon addition of Boc2O.
49
Upon stirring at room temperature for 30 min, the mixture was viscous but free-flowing.

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stirred at that rate for 14 h.50 Concentrated HCl was then added to the stirring mixture in 1-mL portions over 5 min

until pH 2 was reached (10 mL total). The mixture was transferred to a 500-mL separatory funnel and extracted

with Et2O (3 x 100 mL). The combined organic layers were dried over Na2SO4, decanted into a 500-mL round-

bottomed flask, and concentrated under reduced pressure (30 torr → 1 torr). Benzene was added (2 x 20 mL), and

the resulting solution was concentrated under reduced pressure (30 torr → 1 torr) to yield 14–16 g of a pale yellow,

cloudy oil. The residue was partitioned between 1 N aqueous NaOH (100 mL) and Et2O (75 mL) and then

transferred to a 250-mL separatory funnel. The round-bottomed flask was rinsed with two 10-mL portions of 1N

aqueous NaOH that were added to the separatory funnel. The organic layer was removed, and the aqueous layer was

washed with another 75 mL of Et2O.

The aqueous layer was transferred to a 250-mL Erlenmeyer flask and cooled in an ice bath for 2 min. Aqueous HCl

(4 N) was added in 10-mL portions over 5 min until pH 2 was reached (40 mL total). A white precipitate formed

after 35 mL of HCl had been added. The aqueous layer was extracted with diethyl ether (3 x 75 mL), and the

combined organic layers were dried over Na2SO4, decanted into a 500-mL round-bottomed flask, and concentrated

under reduced pressure (30 torr → 1 torr) to yield a white foamy solid. Hexanes (20 mL) was added to the flask,

and the resulting mixture concentrated under reduced pressure. The process was repeated twice to yield a white

powder that was maintained at 1 torr for 2 h. Yield: 7.04–7.51 g (30.4–32.5 mmol, 76–81% yield from

aminodiphenylmethane, range of three experiments). The enantiomeric excess was determined to be 85–86 % by

HPLC analysis of the benzyl ester (range of three experiments). The crude product was heated in a solution of 230–

240 mL 2:1 hexanes/Et2O (32 mL/g) for ~ 2 min. Complete dissolution did not occur. A 5-cm long stirbar was then

added, the flask was capped with a plastic stopper, and the mixture was stirred at 0 °C for 2 h. The mixture was

filtered through a medium porosity fritted disk funnel, and the filtrate was concentrated under reduced pressure to

yield a white foamy solid. Hexanes (20 mL) was added, and the resulting mixture was concentrated to provide a

white solid. Pentane (20 mL) was added, and the resulting mixture was concentrated to provide a white solid that

was maintained at 1 torr for 16 h to provide (R)-Boc-tert-leucine as a white solid: 5.76–6.03 g (24.9–26.1 mmol, 62–

50
After 14 h, the pH 7–8 was reached. The reaction may be monitored as follows: A 50 μL aliquot was removed by
pipette, transferred to a NMR tube, and diluted with 600 μL D2O. 1H-NMR analysis revealed a single resonance at
0.83 ppm, and no other resonances with greater than 5% relative integration between 0.70 and 1.05 ppm.

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65% yield from aminodiphenylmethane, range of three experiments).51 The enantiomeric excess of the filtrate was

determined to be 98–99 % by HPLC analysis of the benzyl ester (range of three experiments); mp: 117–120 °C to

118–121 °C.52,53 [α ]25

D = –5.3° (c 1.5, EtOAc). lit.
54
[α ]25D = + 5.8 (c 0.6, EtOAc, (S)-enantiomer). The compound is
a 6:1 mixture of carbamate rotamers in CDCl3; resonances corresponding to the minor rotamer are indicated with a *

(many resonances for the minor rotamer are indistinguishable from those reported for the major rotamer, and are not
1
reported).55,56 H NMR (500 MHz, CDCl3, 25 °C), δ 5.82 (1H, br s)*, 5.07 (1H, d, J = 9 Hz), 4.12 (1H, d, J = 9.5
13
Hz), 3.90 (1H, br s)*, 1.45 (9H, s), 1.02 (9H, s). C NMR (126 MHz, CDCl3, 25 °C): δ 177.0, 156.8*, 155.8, 81.7*,

80.1, 63.8*, 61.8, 34.6, 34.1*, 28.5, 26.7. IR (cm-1): 3434 (br w), 3309 (w), 3169 (w), 2972 (m), 1740 (m), 1706

(s), 1686 (s), 1640 (s), 1507 (m), 1411 (s), 1368 (m), 1259 (w), 1233 (m), 1211 (w), 1156 (s), 1056 (m), 1008 (m),
+
650 (m), 777 (w), 690 (m). LRMS (ESI): 254.1 (70%) [M+Na] .

51
The primary impurity detected during optimization of this protocol is tert-butyl carbamate, which presumably
originates from ammonia generated during nitrile hydrolysis. Tert-butyl carbamate may be detected by 1H-NMR
spectroscopy as a shoulder on the Ot-Bu resonance of Boc-tert-leucine. Boc-tert-leucine prepared using the
optimized procedure contains no detectable tert-butyl carbamate.
52
The enantiomeric excess of the benzyl ester of the precipitate was 23–29%; mp: 160–166 °C (dec.). The
enantiomeric excess of the benzyl ester of a sample of commercially available Boc-L-(S)-tert-leucine (Fluka) was
>99%; mp 118–122 °C.
53
The synthesis was reproduced on 0.10 mol scale using Procedure B to provide 14.4 g (62 mmol, 62% yield from
aminodiphenylmethane) of Boc-D-(R)-tert-leucine as a white solid; mp: 117–120 °C. The enantiomeric excess of
the product was determined to be 98.5% by HPLC analysis of the benzyl ester.

The 0.10-mol scale synthesis was executed using identical relative amounts of reagents, concentrations, and reaction
times, and required a 1-L separatory funnel, round-bottomed flask, and Erlenmeyer flask.
54
Jenssen, K., Sewald, K. & Sewald, N. Synthesis of marimastat and a marimastat conjugate for affinity
chromatography and surface plasmon resonance studies. Bioconjugate Chem. 15, 594–600 (2004).
55 1
H NMR and 13C NMR spectroscopic data for the major rotamer match previously reported data: Vernall, A. J.,
Steven, B. & Abell, A. D. Cross-metathesis and ring-closing metathesis reactions of amino acid-based substrates.
Tetrahedron, 64, 3980–3997 (2008). The rotameric ratio was not established in this case, and spectroscopic data for
the minor rotamer were not reported.
56
For a discussion on the temperature-, concentration-, and solvent-dependence of rotameric ratios of N-Boc amino
acids, see: Marcovici-Mizrahi, D., Gottlieb, H. E., Marks, V. & Nudelman, A. On the stabilization of the syn-
rotamer of amino acid carbamate derivatives by hydrogen bonding. J. Org. Chem. 61, 8402–8406 (1996).

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Supplementary Figure 3. 1H NMR spectrum of (R)-Boc-tert-leucine

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Supplementary Figure 4. 13C NMR spectrum of (R)-Boc-tert-leucine

Preparation of (R)-benzyl 2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoate for chiral HPLC analysis:

A 2-dram vial containing a small stirbar was charged with Boc-tert-leucine (10 mg, 0.04 mmol), CH2Cl2 (1 mL), 4-

dimethylaminopyridine (2 mg, 0.02 mmol, 0.5 equiv), benzyl alcohol (20 μL, 0.2 mmol, 5 equiv), and EDC (20 mg,

0.1 mmol, 2.5 equiv). The solution was stirred at room temperature for 3 h, and then diluted with 10 mL of diethyl

ether. The mixture was washed with water (2 x 10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL).

The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue can be further

purified by flash column chromatography on silica gel (7:1 hexanes/Et2O). Both the crude and purified samples

were analyzed by chiral HPLC analysis: (AD-H, 1 mL/min, 5% IPA/hexanes, 210 nm): tR(major) = 9.08 min,

tR(minor) = 15.80 min.

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Chiral HPLC analysis of benzyl 2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoate

Racemic (AD-H, 1 mL/min, 5% IPA/hexanes)

Enantiomerically enriched (98.7% ee, purified):

Enantiomerically enriched (98.5% ee, crude):

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(R)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclohexyl)acetic acid

A flame-dried 500-mL round-bottomed flask capped with a rubber septum was charged with anhydrous CH2Cl2 (150

mL) via cannula and cyclohexanecarboxaldehyde57 (9.09 mL, 75 mmol, 1.0 equiv) via syringe under N2. The flask

was cooled in an ice bath for 10 min, the septum was removed, and t-BuOK (10.9 g, 97.5 mmol, 1.3 equiv) was

added in one portion with rapid stirring. The septum was replaced, and iodomethane (14.0 mL, 225 mmol, 3.0

equiv) was added in one portion via syringe. The mixture was stirred at 0 °C under N2 for 30 min. The mixture was

then allowed to warm to room temperature and stirred an additional 2 h. The resulting pale yellow, heterogeneous

mixture was filtered through a 10-cm diameter medium porosity fritted disk funnel, and the cake was washed with

CH2Cl2 (3 x 15 mL). The filtrate was washed with brine (50 mL). The organic layer was dried over Na2SO4 and

concentrated under reduced pressure. The residue was distilled under reduced pressure (1 torr) while maintaining

the receiving flask between –20 to –40 °C (bp < 30 °C). The distillate was a clear, colorless oil that contained (1-

methyl)cyclohexanecarboxaldehyde and 1.25 equiv CH2Cl2, as determined by 1H-NMR analysis: 13.2 g total, ~7.2 g

57
Cyclohexanecarboxaldehyde was purchased from Aldrich and filtered through a cotton plug before use.
Alternatively, cyclohexanecarboxaldehyde may be distilled from CaH2 at 760 torr.

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(1-methyl)cyclohexanecarboxaldehyde (57 mmol, 76% yield).58 The product was used in the next step without

further purification.

A 100-mL round-bottomed flask containing (1-methyl)cyclohexanecarboxaldehyde (57 mmol) was charged with

CH2Cl2 (20 mL), Na2SO4 (10 g), and aminodiphenylmethane (8.83 mL, 51.3 mmol, 0.9 equiv). The flask was

capped with a plastic stopper, and the mixture was stirred at room temperature for 14 h. The reaction mixture was

filtered through a medium porosity fritted disk funnel, rinsing with CH2Cl2 (4 x 10 mL). The filtrate was

concentrated under reduced pressure and maintained at 1 torr with stirring for 1 h to provide a slightly cloudy,

colorless oil. A 5-cm diameter fritted disk funnel was filled with a 3-cm high layer of silica gel. The funnel was

rinsed with a solution of 20:1:0.5 hexanes/diethyl ether/triethylamine (50 mL) under reduced pressure, followed by a

solution of 20:1 hexanes/diethyl ether (50 mL). The oil prepared above was dissolved in 20:1 hexanes/diethyl ether

(25 mL) and rinsed through the frit into a 250-mL round-bottomed flask under reduced pressure. The silica gel was

rinsed with 20:1 hexanes/diethyl ether (4 x 25 mL). The combined mixture was concentrated (30 torr → 1 torr) to

provide a clear, colorless oil that was slightly cloudy. The oil was maintained at 1 torr for 1 h with stirring to

provide (E)-N-((1-methylcyclohexyl)methylene) diphenylmethanamine as a colorless oil with 95 % 1H-NMR purity.

Yield: 14.3 g (49.0 mmol, 96% from aminodiphenylmethane, 65% from cyclohexanecarboxaldehyde).

Caution! HCN is produced. The experiment should be executed in a well-ventilated fume hood. A 250-mL round-

bottomed flask containing a 4-cm long stir bar was charged with KCN (3.26 g, 50 mmol, 2.0 equiv) and toluene (48

mL), capped with a virgin rubber septum, and cooled at 0 °C for 10 min under N2. AcOH (1.72 mL, 30 mmol, 1.2

58
The protocol is a modification of the literature procedure: Anderson, J. C., Denton, R. M., Hickin, H. G. &
Wilson, C. Synthesis of dibenzofuran-1,4-diones using the Dotz benzannulation. Tetrahedron 60, 2327–2335
(2004).

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equiv) and water (1.80 mL, 100 mmol, 4.0 equiv) were added sequentially via syringe, and the N2 inlet was

removed. The resulting white, heterogeneous mixture was stirred vigorously at 0 °C. After 5 min the upper organic

layer had become a clear, colorless solution, and the lower aqueous layer contained a chunky, white precipitate.

After stirring for 20 min, the N2 inlet was restored, and a freshly prepared stock solution of (E)-N-((1-

methylcyclohexyl)methylene)diphenylmethanamine (7.29 g, 25 mmol, 1.0 equiv) and 4e (73 mg, 0.125 mmol,

0.0050 equiv) in toluene (15 mL) was added via syringe over 1 min. The flask containing the stock solution was

rinsed with additional toluene (2 x 2 mL), and the rinses were added to the reaction mixture. The N2 inlet was

removed, and the mixture was stirred at 0 °C. After 4.5 h, the reaction mixture was allowed to warm to room

temperature over 5 min. The septum was removed, and the reaction mixture was treated with 50 mL of a 0.2 g/mL

aqueous K2CO3 solution. The mixture was transferred to a 250-mL separatory funnel, the reaction flask was rinsed

with Et2O (3 x 5 mL), and the rinses were added to the separatory funnel. The organic and aqueous layers were

thoroughly mixed, and the aqueous layer removed. The organic layer was washed with another 50 mL of K2CO3

solution and brine (50 mL). 59 The clear, colorless organic layer was dried over Na2SO4, decanted into a 500-mL

round-bottomed flask, rinsing with Et2O (3 x 5 mL), and concentrated to a volume of 70 mL using a rotary

evaporator. The flask was then charged with a 2-cm long stir bar, placed in a 25 °C water bath, and concentrated to

a volume of approximately 10 mL by vacuum transfer into a –78 °C bath. A sample of the clear, colorless liquid

residue was analyzed by chiral HPLC analysis (AD-H, 1 mL/min, 5% IPA/hexanes, 220 nm), tR(minor) = 5.18 min,

tR(major) = 5.81 min., 89–90% ee (range of two experiments). The liquid was transferred to a 200-mL round-

bottomed flask, rinsing with CH2Cl2 (3 x 4 mL). The solution was concentrated under reduced pressure (~30 torr →

1 torr). The resulting viscous oil was dissolved in CH2Cl2 (2 x 20 mL), and the resulting solution concentrated

under reduced pressure (~30 torr → 1 torr) to a mass of 8.6–8.7 g.60 The crude (R)-2-(benzhydrylamino)-2-(1-

methylcyclohexyl)acetonitrile was used in the next step without further purification.

59
The aqueous layers were disposed in a waste container that was maintained at basic pH and stored in a fume hood.
60 1
H-NMR analysis of the clear, colorless oil revealed <20 mol % remaining toluene. Samples that contained more
toluene provided slightly lower overall yield in the amino acid synthesis. Removal of toluene from the viscous α-
aminonitrile is slow, but addition of CH2Cl2 accelerates this process.

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The 200-mL round-bottomed flask containing (R)-2-(benzhydrylamino)-3,3-dimethylbutanenitrile was charged with

a 4-cm long stirbar. A solution of 60 mL of aqueous 3:1 HCl/H2SO4 solution was generated as follows: a 125-mL

Erlenmeyer flask was charged with deionized water (30 mL) and cooled in an ice bath for 5 min. Concentrated

hydrochloric acid (7.5 mL) was added over 1 min, followed by concentrated sulfuric acid (22.5 mL) over 5 min (in

2-mL portions). The flask was swirled gently, and was allowed to further cool in the ice bath for 5 min. The

solution was then added to the flask containing the α-aminonitrile in one portion, and the flask was fitted with a

chilled reflux condenser. The flask was placed in an oil bath that was maintained at 120 °C, and reaction mixture

was stirred for 68 h.

The flask was cooled to room temperature to yield a dark brown mixture, and then further cooled for 2 min in an ice

bath. Water (50 mL) and diethyl ether (50 mL) were carefully added over 2 min to provide a black upper organic

layer and an orange lower aqueous layer. The entire contents of the flask were poured into a 500-mL separatory

funnel. The flask was rinsed with another 50-mL portion of diethyl ether and another 50-mL portion of water, and

the mixture was added to the separatory funnel. The organic and aqueous layers were thoroughly mixed, and the

aqueous layer was removed. The aqueous layer was further washed with diethyl ether (50 mL), and the combined

aqueous layers were cooled for 5 min in an ice bath within a 1-L Erlenmeyer flask. Aqueous NaOH (4 N) was

added in 10–20-mL portions over 5 min with stirring until pH 10–11 was reached, as determined by pH paper

(approximately 190 mL total).61 The resulting mixture was transferred to a 1-L separatory funnel and washed with

diethyl ether (3 x 50 mL).62 The aqueous layer was transferred to a 1-L Erlenmeyer flask containing a 5-cm long

stirbar, acidified to pH 9.5–10.5 by addition of solid NaHCO3 (1 g), and cooled in an ice bath for 3 min with stirring.

Dioxane (100 mL) was added to the mixture prepared above, followed immediately by Boc2O (16.4 g, 75 mmol, 3.0

equiv) in one portion.63 The flask was covered with Parafilm and allowed to warm to room temperature with

61
The last 30 mL were added in 5-mL portions, and the mixture was thoroughly mixed after each portion had been
added. The pH was checked after each addition to ensure that excess NaOH was not added.
62
The first and second ethereal washes were clear, yellow solutions. The third wash was a clear, nearly colorless
solution.
63
The mixture became viscous upon addition of dioxane, and partially solidified upon addition of Boc2O.

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stirring.64 The stir-rate was adjusted to ensure thorough mixing of the upper organic layer and the lower aqueous

layer, and the mixture was stirred at that rate for 14 h. After 14 h, the pH 7 was reached. Concentrated HCl was

carefully added to stirring mixture in 1-mL portions over 5 min until pH 2 was reached, as determined using pH

paper (10 mL total). The mixture was transferred to a 1-L separatory funnel and extracted with Et2O (3 x 100 mL).

The aqueous layer was viscous but free-flowing, and the organic layer was a clear, colorless solution. The combined

organic layers were dried over Na2SO4, decanted into a 500-mL round-bottomed flask, and concentrated under

reduced pressure (30 torr → 1 torr). Benzene was added (3 x 20 mL), and the resulting solution concentrated under

reduced pressure (30 torr → 1 torr) to yield 12.5 g of a slightly yellow, cloudy oil. The residue was partitioned

between 1 N aqueous NaOH (100 mL) and diethyl ether (75 mL) and transferred to a 250-mL separatory funnel.

The round-bottomed flask was rinsed with two 10-mL portions of 1N aqueous NaOH that were added to the

separatory funnel. The organic layer was removed, and the aqueous layer was washed with another 75 mL diethyl

ether.

The aqueous layer was transferred to a 250-mL Erlenmeyer flask and cooled in an ice bath for 2 min. Aqueous HCl

(4 N) was added in 10-mL portions over 5 min until pH ~ 2 was reached (40 mL total). A white precipitate formed

after 35 mL of HCl solution had been added. The aqueous layer was extracted with diethyl ether (3 x 75 mL), and

the combined clear, colorless organic layers were dried over Na2SO4, decanted into a 500-mL round-bottomed flask,

and concentrated under reduced pressure (30 torr → 1 torr) to yield a white foamy solid. Benzene (2 x 20 mL) was

added to the flask, and the resulting mixture was was concentrated under reduced pressure. The process was

repeated with hexanes (4 x 20 mL) to yield a white powder that was maintained at 1 torr for 1 h. Yield: 4.30–4.33 g

(15.8–16.0 mmol, 63–64% yield from imine). The enantiomeric excess was determined to be 87–88 % by HPLC

analysis of the benzyl ester (range of two experiments).

The crude product was heated in a solution of 170 mL of 3:1 hexanes/Et2O for 2 min. Complete dissolution did not

occur. A 5-cm long stirbar was then added, the flask was capped with a plastic stopper, and the mixture was stirred

at 0 °C for 2h. The mixture was filtered through a medium porosity fritted funnel and the filtrate was concentrated

under reduced pressure to yield a white foamy solid. Hexanes (3 x 20 mL) was added, and the resulting mixture was

concentrated to provide a white solid. Pentane (20 mL) was added, and the resulting mixture was concentrated to

64
Upon stirring at room temperature for 30 min, the mixture was viscous but free-flowing.

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provide a white solid that was maintained at 1 torr for 6 h to provide (R)-2-(tert-butoxycarbonylamino)-2-(1-

methylcyclohexyl)acetic acid as a white powder: 3.43–3.52 g (12.6–13.0 mmol, 51–52% yield from imine, range of

two experiments); mp 127–130 °C to 128–130 °C. The enantiomeric excess of the filtrate was determined to be 98–
1
99 % by HPLC analysis of the benzyl ester (see below). H-NMR analysis revealed ~ 1 mass % residual

hexanes/pentane.65 [α ]25
D = –15.2° (c 1.5, EtOAc). The compound exists as a 10:1 mixture of carbamate rotamers in

CDCl3; resonances corresponding to the minor rotamer are indicated with a * (resonances that are indistinguishable
1
from those corresponding to the major rotamer are not reported). H NMR (500 MHz, CDCl3, 25 °C), δ 5.60 (1H, br

s)*, 5.04 (1H, d, J = 9 Hz), 4.30 (1H, d, J = 9 Hz), 4.08 (1H, br s)*, 1.60–1.32 (10H, m), 1.45 (9H, s), 0.95 (3H, s).
13
C NMR (126 MHz, CDCl3, 25 °C): δ 177.2, 156.7*, 155.8, 81.6*, 80.1, 62.4*, 60.7, 37.2, 36.8*, 34.9, 34.7, 28.5,

26.0, 21.8, 21.7, 20.5. IR (cm-1): 3432 (w), 3312 (m), 2935 (m), 1737 (m), 1704 (s), 1640 (m), 1502 (m), 1409 (s),
+
1367 (m), 1231 (m), 1156 (s), 1026 (m), 844 (m), 777 (w), 685 (m). LRMS (ESI): 294.2 (100%) [M+Na] .

65
The enantiomeric excess of the benzyl ester of the precipitate was 35–36%.

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Supplementary Figure 5. 1H NMR spectrum of (R)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclohexyl)acetic

acid

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Supplementary Figure 6. 13C NMR spectrum of (R)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclohexyl)acetic

acid

Preparation of (R)-benzyl 2-(tert-butoxycarbonylamino)-2-(1-methylcyclohexyl)acetate for chiral HPLC analysis:

A 2-dram vial containing a small stirbar was charged with (R)-2-(tert-butoxycarbonylamino)-2-(1-

methylcyclohexyl)acetic acid (11 mg, 0.04 mmol), CH2Cl2 (1 mL), 4-dimethylaminopyridine (2 mg, 0.02 mmol, 0.5

equiv), benzyl alcohol (20 μL, 0.2 mmol, 5 equiv), and EDC (20 mg, 0.1 mmol, 2.5 equiv). The solution was stirred

at room temperature for 3 h, and then diluted with 10 mL Et2O. The mixture was washed with water (2 x 10 mL),

saturated aqueous NaHCO3 (10 mL), and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated

under reduced pressure. The residue was purified by flash column chromatography on silica gel (7:1 hexanes/Et2O)

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and analyzed by chiral HPLC analysis: (AS-H, 1 mL/min, 2% IPA/hexanes, 210 nm): tR(minor) = 6.84 min,

tR(major) = 8.13 min.

Chiral HPLC analysis of Benzyl 2-(tert-butoxycarbonylamino)-2-(1-methylcyclohexyl)acetate

Racemic (AS-H, 1 mL/min, 2% IPA/hexanes):

Enantiomerically enriched (98.7% ee):

(R)-2-(tert-butoxycarbonylamino)-3-ethyl-3-methylpentanoic acid

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An oven-dried 500-mL round-bottomed flask capped with a rubber septum was charged with anhydrous CH2Cl2

(250 mL) and 2-ethylbutyraldehyde66 (12.3 mL, 100 mmol, 1.0 equiv) via syringe under N2. The flask was cooled in

an ice bath for 10 min, the septum was removed, and t-BuOK (14.6 g, 130 mmol, 1.3 equiv) was added in one

portion with rapid stirring. The septum was replaced, and iodomethane (18.7 mL, 300 mmol, 3.0 equiv) was added

in one portion via syringe. The mixture was stirred at 0 °C for 30 min. The mixture was then stirred at room

temperature for 2 h. The resulting slightly yellow, heterogeneous mixture was filtered through a 10-cm diameter

medium porosity fritted disk funnel, and the cake was washed with CH2Cl2 (3 x 15 mL). The filtrate was washed

with brine (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The

residue was distilled under reduced pressure (~1 torr) while maintaining the receiving flask between –20 to –40 °C

(bp <30 °C). The distillate (13.5 g) was a clear, colorless oil that contained CH2Cl2 (0.3 equiv) and t-BuOH (0.2
1
equiv), and was used without further purification. The purity of the compound was assessed by H NMR

spectroscopy (400 MHz, CDCl3): δ 9.42 (1H, s), 5.30 (0.64 H, s, CH2Cl2), 1.58–1.45 (4H, m), 1.27 (1.97H, s, t-

BuOH), 0.98 (3H, s), 0.81 (6H, t, J = 8 Hz).

A 100-mL round-bottomed flask containing crude 2-ethyl-2-methylbutanal was charged with CH2Cl2 (20 mL) and

Na2SO4 (10 g). Aminodiphenylmethane (8.83 mL, 80 mmol, 0.80 equiv) was added via syringe. The flask was

capped with a plastic stopper, and the mixture was stirred at room temperature for 14 h. The reaction mixture was

filtered through a medium porosity fritted disk funnel and rinsed with CH2Cl2 (4 x 10 mL). The filtrate was

concentrated under reduced pressure and maintained at 1 torr with stirring for 1 h to provide a slightly cloudy,

colorless oil. A 5-cm diameter fritted disk funnel was filled with a 3-cm high layer of silica gel. The funnel was

rinsed with a solution of 20:1:0.5 hexanes/Et2O/triethylamine (50 mL) under reduced pressure, followed by a

solution of 20:1 hexanes/Et2O (50 mL). The oil prepared above was dissolved in 20:1 hexanes/Et2O (25 mL) and

rinsed through the frit into a 250-mL round-bottomed flask under reduced pressure, rinsing with 20:1 hexanes/Et2O

(4 x 25 mL). The mixture was concentrated under reduced pressure (30 torr → 1 torr) to provide a clear, colorless

66
2-Ethylbutyraldehyde (~92 %) was purchased from Aldrich and used without further purification.

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oil that was slightly cloudy. The oil was maintained at 1 torr for 1 h while stirring to provide (E)-N-(2-ethyl-2-

methylbutylidene)diphenylmethanamine in 95 % 1H-NMR purity.67 Yield: 18.7 g (67 mmol, 84% from

aminodiphenylmethane, 67% from 2-ethyl-2-butanal).

Caution! HCN is produced. The experiment should be executed in a well-ventilated fume hood. A 250-mL round-

bottomed flask containing a 4-cm long stir bar was charged with KCN (3.26 g, 50 mmol, 2.0 equiv) and toluene (48

mL), capped with a virgin rubber septum, and cooled at 0 °C for 10 min under N2. AcOH (1.72 mL, 1.2 equiv, 30

mmol) and water (1.80 mL, 4.0 equiv, 160 mmol) were added sequentially via syringe, and the N2 inlet was

removed. The resulting white, heterogeneous mixture was stirred vigorously at 0 °C. After 5 min the upper organic

layer had become a clear, colorless solution, and the lower aqueous layer contained a chunky, white precipitate.

After stirring for 20 min, the N2 inlet was restored, and a freshly prepared stock solution of (E)-N-(2-ethyl-2-

methylbutylidene)diphenylmethanamine (6.90 g, 25 mmol, 1.0 equiv) and 4e (73 mg, 0.125 mmol, 0.0050 equiv) in

toluene (15 mL) was added via syringe over 1 min. The stock solution was rinsed with additional toluene (2 x 2

mL). The N2 inlet was removed, and the mixture was stirred at 0 °C. After an additional 6 h, the reaction mixture

was allowed to warm to room temperature for 5 min. The septum was removed, and the reaction mixture was

treated with 50 mL of a 0.2 g/mL aqueous K2CO3 solution. The mixture was transferred to a 250-mL seperatory

funnel, the reaction flask was rinsed with Et2O (3 x 5 mL), and the rinses were added to the separatory funnel. The

organic and aqueous layers were thoroughly mixed, and the aqueous layer removed. The organic layer was washed

with another 50 mL of K2CO3 solution and brine (50 mL). 68 The clear, colorless organic layer was dried over

Na2SO4, decanted into a 500-mL round-bottomed flask, rinsing with Et2O (3 x 5 mL), and concentrated at ~30 torr

to a volume of approximately 70 mL using a rotary evaporator. The flask was then charged with a 2-cm long stir

bar, placed in a 25 °C water bath, and concentrated to a volume of 10 mL by vacuum transfer into a –78 °C bath. A

67
Characterization data for (E)-N-(2-ethyl-2-methylbutylidene)diphenylmethanamine are provided above.
68
The aqueous layers were disposed in a waste container that was maintained at basic pH and stored in a fume hood.

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sample of the clear, colorless liquid residue was analyzed by chiral HPLC analysis (AS-H, 1 mL/min, 1%

IPA/hexanes, 220 nm): 88% ee. The liquid was transferred to a 200-mL round-bottomed flask, rinsing with CH2Cl2

(3 x 4 mL). The solution was concentrated under reduced pressure (~30 torr → 1 torr). The residue was dissolved

in CH2Cl2 (2 x 20 mL), and the resulting solution concentrated under reduced pressure (~30 torr → 1 torr) to a mass
1
of 8.5 g of a colorless oil (ca. 90% H-NMR purity). The crude (S)-2-(benzhydrylamino)-3-ethyl-3-

methylpentanenitrile was used in the next step without further purification.69

The 200-mL round-bottomed flask containing (R)-2-(benzhydrylamino)-3-ethyl-3-methylpentanenitrile was charged

with a 4-cm long stirbar. A solution of 60 mL of aqueous HCl/H2SO4 solution was generated as follows: a 125-mL

Erlenmeyer flask was charged with deionized water (30 mL) and cooled in an ice bath for 5 min. Concentrated

hydrochloric acid (7.5 mL) was added over 1 min, followed by concentrated sulfuric acid (22.5 mL) over 5 min (in

2-mL portions). The flask was swirled gently and was allowed to further cool in the ice bath for 5 min. The

solution was then added to the flask containing the α-aminonitrile in one portion, and the flask was fitted with a

chilled reflux condenser. The flask was placed in an oil bath that was maintained at 120 °C, and reaction mixture

was stirred for 68 h.

After 68h, the flask was cooled to room temperature to yield a dark brown mixture that was further cooled in an ice

bath for 2 min. Water (50 mL) and diethyl ether (50 mL) were carefully added over 2 min to provide a dark orange

organic layer and a light orange lower aqueous layer. The entire contents of the flask were poured into a 500-mL

separatory funnel. The flask was rinsed with another 50-mL portion of diethyl ether and another 50-mL portion of

water, and the mixture was added to the separatory funnel. The organic and aqueous layers were thoroughly mixed,

and the aqueous layer was removed. The organic layer was further washed with diethyl ether (50 mL), and the

combined aqueous layers were cooled for 5 min in an ice bath within a 1-L Erlenmeyer flask. Aqueous NaOH (4 N)

was added in 10–20-mL portions over 5 min with stirring until pH ~ 12–13 was reached, as determined by pH paper

69
Characterization data for (S)-2-(benzhydrylamino)-3-ethyl-3-methylpentanenitrile are provided above.

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(190 mL total). 70 The resulting mixture was transferred to a 1-L separatory funnel and washed with diethyl ether (2

x 50 mL). The aqueous layer was transferred to a 1-L Erlenmeyer flask containing a 5-cm long stirbar, acidified to

pH 9.5–10.5 by addition of solid NaHCO3 (1 g), and cooled in an ice bath for 3 min with stirring.

Dioxane (100 mL) was added, followed immediately by Boc2O (16.4 g) in one portion. The mixture became

viscous upon addition of dioxane and partially solidified upon addition of Boc2O. The flask was covered with

Parafilm and allowed to warm to room temperature while stirring. Upon stirring at room temperature for 30 min, the

mixture was viscous but free-flowing. The stir-rate was adjusted to ensure thorough mixing of the upper organic

layer and the lower aqueous layer, and the mixture was stirred at that rate for 14 h. After 14 h, the pH 7 was

reached. Concentrated HCl was carefully added to stirring mixture in 1-mL portions over 5 min until pH 2 was

reached, as determined by pH paper (~10 mL total). The mixture was transferred to a 1-L separatory funnel and

extracted with Et2O (3 x 100 mL). The aqueous layer was viscous but free-flowing, and the organic layer was a

clear, colorless solution. The combined organic layers were dried over Na2SO4, decanted into a 500-mL round-

bottomed flask, and concentrated under reduced pressure (30 torr → 1 torr). Benzene was added (3 x 20 mL), and

the resulting solution was concentrated under reduced pressure (30 torr → 1 torr) to yield 10 g of viscous yellow

solid. The residue was partitioned between 1 N aqueous NaOH (100 mL) and diethyl ether (75 mL) and transferred

to a 250-mL separatory funnel. The round-bottomed flask was rinsed with two 10-mL portions of 1N aqueous

NaOH that were added to the separatory funnel. The aqueous layer was removed, and the organic layer was washed

with 0.5 N NaOH (50 mL).

The aqueous layer was transferred to a 250-mL Erlenmeyer flask and cooled in an ice bath for 2 min. Aqueous HCl

(4 N) was added in 10-mL portions over 5 min until pH 2 was reached (40 mL total). A white precipitate formed

after 35 mL of HCl solution had been added. The aqueous layer was extracted with diethyl ether (3 x 75 mL), and

the combined clear, colorless organic layers were dried over Na2SO4, decanted into a 500-mL round-bottomed flask,

and concentrated under reduced pressure (~30 torr → 1 torr) to yield 5.5 g of a white foamy solid that was

maintained at 1 torr for 30 min.

70
The last 30 mL were added in 5-mL portions, and the mixture was thoroughly mixed after each portion had been
added. The pH was checked after each addition to ensure that excess NaOH was not added.

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The foamy solid was dissolved in diethyl ether (150 mL), and t-BuNH2 (2.5 mL) was added via syringe. A white

precipitate formed, the flask was placed in an ice bath, and the mixture was stirred for 45 min. The mixture was

filtered through a 10-cm diameter Buchner funnel, rinsing with ice cold Et2O (3 x 25 mL). The white precipitate

was transferred to a 500-mL round-bottomed flask and maintained at 1 torr for 2 h (6.1 g, 18.3 mmol). The product

was taken up in THF (100 mL), heated to reflux, and treated with EtOH in 1–2-mL portions until the solid dissolved

completely (~15 mL EtOH total). The flask was capped with a plastic stopper and allowed to cool to room

temperature for 30 min. The flask was transferred to a 4 °C refrigerator and maintained at that temperature for 16 h.

The fluffy white precipitate was isolated by filtration on a 10-cm diameter Buchner funnel, rinsing with ice cold

THF (3 x 25 mL). The precipitate was transferred to a 200-mL round-bottomed flask and maintained at 1 torr for 4

h. Yield: 3.96–4.23 g (11.9–12.7 mmol, 48–51% yield from imine). The enantiomeric excess was determined to be

98–99% by HPLC analysis of the benzyl ester (range of two experiments).

The free acid was isolated by partitioning the salt (100 mg) between aqueous 1 N HCl (10 mL) and diethyl ether (10

mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo to provide

(R)-2-(tert-butoxycarbonylamino)-3-ethyl-3-methylpentanoic acid as a viscous, colorless oil (> 90% recovery).

[α ]25D = –11.6° (c 2.0, EtOAc). The compound exists as a 6:1 mixture of rotamers in CDCl3; resonances

corresponding to the minor rotamer are indicated with a * (many resonances for the minor rotamer are
1
indistinguishable from those reported for the major rotamer, and are not reported). H NMR (500 MHz, CDCl3):

δ 5.63 (1H, br s)*, 5.00 (1H, d, J = 9.5 Hz), 4.31 (1H, d, J = 9.0 Hz), 4.08 (1H, br s)*, 1.44 (9H, s), 1.41–1.38 (4H,
13
m), 0.90 (3H, s), 0.88–0.84 (6H, m). C{1H} NMR (100 MHz, CDCl3: δ 177.7, 156.6*, 155.8, 81.6*, 80.1, 60.4*,

58.8, 39.7, 39.3*, 28.5, 28.3, 27.9, 20.3. IR (cm-1): 2971 (m), 1709 (s), 1656 (s), 1503 (m), 1395 (m), 1368 (m),
+
1244 (w), 1161 (s), 909 (m), 731 (m). LRMS (ESI): 282.2 (100%) [M+Na] .

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Supplementary Figure 7. 1H NMR spectrum of (R)-2-(tert-butoxycarbonylamino)-3-ethyl-3-methylpentanoic acid

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Supplementary Figure 8. 13C NMR spectrum of (R)-2-(tert-butoxycarbonylamino)-3-ethyl-3-methylpentanoic acid

Preparation of (R)-benzyl 2-(tert-butoxycarbonylamino)-3-ethyl-3-methylpentanoate for chiral HPLC analysis

A 2-dram vial containing a small stir bar was charged with (R)-2-(tert-butoxycarbonylamino)-3-ethyl-3-

methylpentanoic acid (10 mg, 0.04 mmol), CH2Cl2 (1 mL), 4-dimethylaminopyridine (2 mg, 0.02 mmol, 0.5 equiv),

benzyl alcohol (20 μL, 0.2 mmol, 5 equiv), and EDC (20 mg, 0.1 mmol, 2.5 equiv). The solution was stirred at

room temperature for 3 h, and then diluted with 10 mL Et2O. The mixture was washed with water (2 x 10 mL),

saturated aqueous NaHCO3 (10 mL), and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated

under reduced pressure. The residue was purified by flash column chromatography on silica gel (7:1 hexanes/Et2O)

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and analyzed by chiral HPLC analysis: (AD-H, 1 mL/min, 5% IPA/hexanes, 210 nm): tR(major) = 10.42 min,

tR(minor) = 12.87 min.

Chiral HPLC analysis of (R)-benzyl 2-(tert-butoxycarbonylamino)-3-ethyl-3-methylpentanoate

Racemic (AD-H, 1 mL/min, 5% IPA/hexanes):

Enantiomerically enriched (97.9% ee):

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Calculation of intermediate in imine hydrocyanation mechanism

Calculations were executed using the Gaussian 03 program71 at the B3LYP/6-31G(d) level of density functional

theory. The structure shown below is an intermediate on the potential energy surface leading to (R)-3a (left) that

directly precedes the C–C bond forming step. The catalyst structure used in this calculation is an analogue of 4e in

which the trifluoromethyl groups have been replaced with protons. The structure was characterized by harmonic

frequency calculation and shown to have no imaginary frequencies.

Supplementary Table 1. Coordinates of calculated intermediate in imine hydrocyanation mechanism

N -3.62351300 -1.60701800 -0.98824600

H -3.62272100 -0.61778900 -1.27926500
C -2.41733300 -2.21975000 -1.16298300
N -1.52241500 -1.38473100 -1.77411600
H -1.80668000 -0.40561900 -1.87265300
S -2.01081400 -3.80420000 -0.69691900
N -0.43640600 2.28657000 0.49130900
C -1.28193600 2.52103900 1.42578000
H -0.21638600 1.31250200 0.20453700
C -2.65801500 2.28041200 -1.80540000
N -3.01824600 1.17097400 -1.62777900
C 0.17974500 3.31507400 -0.40898700
H -0.27226700 3.06698400 -1.37646300

71
Gaussian 03, Revision E.01, Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A.,
Cheeseman, J. R., Montgomery, Jr., J. A., Vreven, T., Kudin, K. N., Burant, J. C., Millam, J. M., Iyengar, S. S.,
Tomasi, J., Barone, V., Mennucci, B., Cossi, M., Scalmani, G., Rega, N., Petersson, G. A., Nakatsuji, H., Hada, M.,
Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Klene,
M., Li, X., Knox, J. E., Hratchian, H. P., Cross, J. B., Bakken, V., Adamo, C., Jaramillo, J., Gomperts, R.,
Stratmann, R. E., Yazyev, O., Austin, A. J., Cammi, R., Pomelli, C., Ochterski, J. W., Ayala, P. Y., Morokuma, K.,
Voth, G. A., Salvador, P., Dannenberg, J. J., Zakrzewski, V. G., Dapprich, S., Daniels, A. D., Strain, M. C., Farkas,
O., Malick, D. K., Rabuck, A. D., Raghavachari, K., Foresman, J. B., Ortiz, J. V., Cui, Q., Baboul, A. G., Clifford,
S., Cioslowski, J., Stefanov, B. B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Martin, R. L., Fox, D. J.,
Keith, T., Al-Laham, M. A., Peng, C. Y., Nanayakkara, A., Challacombe, M., Gill, P. M. W., Johnson, B., Chen, W.,
Wong, M. W., Gonzalez, C., & Pople, J. A., Gaussian, Inc., Wallingford CT, 2004.

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C -0.14854800 -1.72923000 -2.07964300

H -0.12626500 -2.81275100 -2.17437600
C 0.30496900 -1.14434600 -3.46788300
C 0.75390900 -1.28182100 -0.90705800
O 0.63840700 -0.12974000 -0.44927100
N 1.67454200 -2.14602700 -0.39787700
C 1.80016400 -3.55406800 -0.79613300
H 2.27989600 -4.09793600 0.01841200
H 0.81379300 -3.99520100 -0.95081600
H 2.41754800 -3.66911700 -1.69265500
C 2.59117300 -1.64722600 0.65479300
H 2.47951600 -0.56112200 0.60989000
H -1.49067400 3.57111600 1.62240400
C 1.68420700 3.10945100 -0.48179500
C 2.33714100 3.38609300 -1.68946800
C 2.44453000 2.70927400 0.62353000
C 3.72333000 3.27180300 -1.78937900
H 1.75502800 3.69636400 -2.55344600
C 3.83259700 2.59083000 0.52379200
H 1.95567200 2.47998800 1.56658900
C 4.47588900 2.87438100 -0.68189000
H 4.21440400 3.49023800 -2.73361800
H 4.40973000 2.27659200 1.38908400
H 5.55593100 2.78418200 -0.75794600
C -0.24253400 4.73775600 -0.05396500
C -1.42768900 5.24299300 -0.61276600
C 0.51395500 5.54747400 0.80439600
C -1.84220600 6.54140200 -0.31320200
H -2.01972300 4.59487500 -1.25813800
C 0.09180400 6.84385300 1.10279400
H 1.44400000 5.17567700 1.22393300
C -1.08539100 7.34408300 0.54301200
H -2.75798300 6.92589200 -0.75405800
H 0.68905300 7.46537700 1.76458000
H -1.40887400 8.35630600 0.77107800
C 2.16843200 -2.08086400 2.06116000
C 0.97641100 -2.77243600 2.30683100
C 2.96486200 -1.70915000 3.15654900
C 0.60028500 -3.09981600 3.61350400
H 0.32433600 -3.05099400 1.48422300
C 2.58713300 -2.03054900 4.45893500
H 3.89265800 -1.16888100 2.98538100
C 1.40219700 -2.73327800 4.69293000
H -0.32664200 -3.64253800 3.77845600
H 3.22019800 -1.73417100 5.29153500
H 1.10884500 -2.98996800 5.70741500
C 4.04339400 -1.96485800 0.28752600
C 4.69811800 -1.12933800 -0.62925200
C 4.73598300 -3.06967400 0.79834500
C 6.00669900 -1.39477600 -1.03199000
H 4.17766200 -0.26033400 -1.02450800
C 6.04668500 -3.33708800 0.39752300
H 4.25474700 -3.71847500 1.52420900
C 6.68570000 -2.50239100 -0.51981000
H 6.49744800 -0.73409000 -1.74198400
H 6.56760000 -4.19950200 0.80507200

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H 7.70629400 -2.71022100 -0.82989000

C 1.72534400 -1.65408400 -3.78606200
H 2.46245100 -1.32138700 -3.04617600
H 1.75861900 -2.74908800 -3.83289600
H 2.04693400 -1.27437200 -4.76265600
C -0.66311100 -1.68205200 -4.54182800
H -1.68122400 -1.31475300 -4.38601500
H -0.33403200 -1.35757200 -5.53610300
H -0.69549900 -2.77817000 -4.53769600
C 0.30388700 0.39614200 -3.50992200
H 1.02424400 0.81946500 -2.80409700
H 0.58285900 0.72857400 -4.51762400
H -0.68048600 0.82172400 -3.28868300
C -2.02139400 1.51463400 2.25131800
C -1.70126400 1.82509000 3.73552500
H -1.92441800 2.86688600 3.99403300
H -2.31621200 1.18165500 4.37316900
H -0.64952500 1.62595500 3.96963400
C -3.52635200 1.78610300 1.97317800
H -3.75338400 1.65367300 0.91158500
H -4.12445400 1.07700000 2.55530100
H -3.81469000 2.80109900 2.27110000
C -1.66680100 0.06186300 1.91317000
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