optical resolution via catalytic generation of chiral ... · s2 experimental section general. all...

Supporting Information �

S1�

Optical Resolution via Catalytic Generation of Chiral Auxiliary

Hiroki Kiyama, Tsubasa Inokuma, Yusuke Kuroda, Yousuke Yamaoka, Kiyosei Takasu,

and Ken-ichi Yamada*

Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Kyoto 606-8501, Japan.

Graduate School of Pharmaceutical Sciences, Tokushima University, Shomachi, Tokushima

770-8505, Japan

E-mail: [email protected]

Table of Contents

Experimental Section General Information .............................................................................................................. S2 Starting Materials .................................................................................................................. S2 General Procedure for the Catalytic Asymmetric Addition of Alcohol 1 to Imine 2 ............ S2 Hydrolysis of 4a and 5a ........................................................................................................ S4

NMR Spectra and HPLC Traces 4a ........................................................................................................................................... S5 5a ........................................................................................................................................... S8 4b ......................................................................................................................................... S11 5b ......................................................................................................................................... S13 4c ......................................................................................................................................... S16 5c ......................................................................................................................................... S18 1a ......................................................................................................................................... S21


S2�

Experimental Section General. All melting points are uncorrected. Silica gel was used for column chromatography. NMR (500 and 125

MHz for 1H and 13C, respectively) was measured in CDCl3. Chemical shifts (δ) and coupling constants (J) are

presented in parts per million relative to tetramethylsilane (0 ppm for 1H) or CDCl3 (77.0 ppm for 13C), and hertz,

respectively. Abbreviations are as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad. The wave

numbers of maximum absorption peaks of IR spectroscopy are presented in cm−1. TOF mass spectrometers were

used for ESIMS. Commercially available solvents and reagents were purchased and used without purification

except for chloroform, from which EtOH was removed by being washed with water, dried over P2O5, and distilled

prior to use.

Starting Materials. Alcohols 1a1 and 1c,2 imine 2,3 chiral phosphoric acids4 were prepared according to the

literatures. Catalyst 3a and 3b were prepared from the chiral phosphoric acids as described in the text.

General Procedure for the Catalytic Asymmetric Addition of Alcohol 1 to Imine 2 (Table 1, entry 8): To

alcohol 1 (0.20 mmol), imine 2 (0.40 mmol, 2.0 equiv), and MgSO4 (50 mg) was added a solution of 3 (1 mol %) in

ethyl acetate (1 mL) under Ar atmosphere at rt. The reaction mixture was stirred for 1 h, diluted with hexane (4

mL), filtered through pad of silica gel, and concentrated in vacuo. The diastereomeric ratio was determined by 1H

NMR of the resulting residue, which was then purified by silica gel flash chromatography to provide 4 and 5. The

enantiomeric ratio was determined by chiral stationary phase HPLC analysis.

N-((R)-((1R,2S)-2-Benzylcyclohexyloxy)(phenyl)methyl)benzamide (4a): Purified by silica

gel column chromatography (hexane/EtOAc 40:1 to 10:1) followed by recrystallization from

hexane/EtOAc. 99% ee (Daicel Chiralpak IA; 254 nm; hexane/i-PrOH 95:5, 1.0 mL/min; tr

major 13.8 min, minor 22.1 min). Colorless plates of mp 147–149 °C. [α]D20

+40.3 (c 1.00,

CHCl3). 1H NMR: 0.93 (m, 1H), 1.06 (m, 1H), 1.26 (m, 1H), 1.43 (m, 1H), 1.54 (m, 1H), 1.60

(m, 2H), 1.72 (m, 2H), 2.20 (m, 2H), 3.29 (dd, J = 13.0, 3.5, 1H), 3.52 (m, 1H), 6.63 (d, J = 9.0, 1H), 6.70 (m, 1H),

7.13 (d, J = 7.5, 2H), 7.17 (d, J = 7.5, 1H), 7.24 (d, J = 7.5, 2H), 7.33 (t, J = 7.5, 1H), 7.39 (t, J = 7.5, 2H), 7.46 (t, J

= 7.5, 2H), 7.53 (t, J = 7.5, 1H), 7.58 (d, J = 7.5, 2H), 7.81 (d, J = 7.5, 2H). 13C NMR: 24.82, 24.94, 29.58, 33.17,

38.80, 45.46, 80.73, 82.26, 125.61, 126.01, 127.04, 128.10, 128.41, 128.63, 128.70, 129.25, 131.92, 133.97, 140.12,

140.99, 166.58. IR (KBr): 2936, 2859, 2361, 2338, 1643, 1605, 1578, 1520, 1485, 1450, 1038, 760. HRMS–ESI

(m/z): [M + H]+ calcd for C27H28NO2, 398.2125; found, 398.2127. The absolute configuration of the aminal moiety

was assigned based on the reported selectivity of the asymmetric addition.5 The absolute configuration of the

��

1. Hazmi, A. M. A.; Sheikh, N. S.; Bataille, C. J. R.; Al-Hadedi, A. A. M.; Watkin, S. V.; Luker, T. J.; Camp, N. P.; Brown, R. C. D. Org. Lett. 2014, 16, 5104. 2. Alexakis, A.; Jachiet, D.; Normant, J. F. Tetrahedron 1986, 42, 5607. 3. (a) Cowen, B. J.; Saunders, L. B.; Miller, S. J. J. Am. Chem. Soc. 2009, 131, 6105. (b) Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J. J. Am. Chem. Soc. 2001, 123, 9696. 4. (a) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2005, 127,9360. (b) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem. Int. Ed. 2005, 44, 7424. (c) Akiyama, T.; Tamura, Y.; Itoh, J.; Morita, H.; Fuchibe, K. Synlett 2006, 141. 5. Nimmagadda, S. K.; Zhang, Z.; Antilla, J. C. Org. Lett. 2014, 16, 4098.

Bn

Ph NHBz

O H


S3�

cyclohexanol moiety was determined after hydrolysis to (1R,2S)-1a (vide infra).

N-((R)-((1S,2R)-2-Benzylcyclohexyloxy)(phenyl)methyl)benzamide (5a): Purified by silica

gel column chromatography (hexane/EtOAc 40:1 to 10:1). 94% ee (Daicel Chiralpak IA; 254

nm; hexane/i-PrOH 95:5, 1.0 mL/min; tr major 11.9 min, minor 17.9 min). Colorless

amorphous. [α]D20

+66.4 (c 1.10, CHCl3). 1H NMR: 0.91 (m, 1H), 1.07 (d, J = 12.0, 1H), 1.28

(m, 2H), 1.56 (d, J = 13.0, 1H), 1.65 (d, J = 13.0, 1H), 1.72 (dd, J = 20.8, 10.2, 2H), 2.19 (dd, J

= 13.0, 10.2, 1H), 2.31 (d, J = 9.5, 1H), 3.38 (dd, J = 13.0, 3.0, 1H), 3.52 (m, 1H), 6.67 (s, 2H), 7.15 (d, J = 7.7,

3H), 7.24 (m, 2H), 7.33 (d, J = 7.2, 1H), 7.38 (t, J = 7.3, 2H), 7.42 (t, J = 7.6, 2H), 7.52 (dd, J = 18.0, 7.5, 3H), 7.78

(d, J = 7.5, 2H). 13C NMR: 24.60, 25.19, 30.01, 31.25, 39.09, 44.72, 76.74, 79.51, 125.56, 126.00, 126.99, 128.05,

128.26, 128.48, 128.66, 129.22, 131.90, 133.79, 140.40, 141.14, 167.18. IR (KBr): 2928, 2859, 2361, 2338, 1643,

1524, 1485, 1450, 1350, 1045, 764. HRMS–ESI (m/z): [M + Na]+ calcd for C27H29NO2Na, 422.2029; found,

422.2086. The absolute configuration of the aminal moiety was assigned based on the reported selectivity of the

asymmetric addition.5 The absolute configuration of the cyclohexanol moiety was determined after hydrolysis to

(1S,2R)-1a (vide infra).

N-((R)-phenyl((1R,2S)-2-phenylcyclohexyloxy)methyl)benzamide (4b): Purified by column

chromatography (hexane/toluene/EtOAc 10:10:1). 92% ee (Daicel Chiralpak AD-H; 254 nm;

hexane/i-PrOH 95:5, 0.8 mL/min; tr major 13.9 min, minor 23.1 min). Colorless solids of mp

128–130 °C. [α]D20

–1.6 (c 0.58, CHCl3). 1H NMR: 1.29–1.63 (m, 4H), 1.72 (m, 1H), 1.83 (m,

1H), 1.90 (m, 1H), 2.31 (dd, J = 12.5, 3.3, 1H), 2.63 (m, 1H), 3.88 (td, J = 10.4, 4.2, 1H), 6.14

(d, J = 9.0, 1H), 6.56 (d, J = 9.0, 1H), 6.84 (d, J = 7.2, 2H), 7.12 (t, J = 7.3, 2H), 7.15–7.24 (m, 2H), 7.26–7.29 (m,

4H), 7.44 (t, J = 7.5, 2H), 7.52 (t, J = 7.5, 1H), 7.75–7.79 (m, 2H). 13C NMR: 25.16, 25.84, 33.81, 34.02, 51.71,

80.51, 82.21, 125.80, 126.26, 126.99, 127.93, 128.07, 128.11, 128.28, 128.67, 131.87, 133.96, 139.42, 144.33,

166.53. IR (KBr): 2928, 1667, 1508, 1481, 1450, 1342, 1215, 1065. HRMS–ESI (m/z): [M + Na]+ calcd for

C26H27NO2Na, 408.1934; found, 408.1938. The absolute configuration of the aminal moiety was assigned based on

the reported selectivity of the asymmetric addition.5 The absolute configuration of the cyclohexanol moiety was

determined after hydrolysis to (1R,2S)-1b.6

N-((R)-phenyl((1S,2R)-2-phenylcyclohexyloxy)methyl)benzamide (5b): Purified by column

chromatography (hexane/toluene/EtOAc 10:10:1). 93% ee (Daicel Chiralpak AD-H; 254 nm;

hexane/i-PrOH 95:5, 0.8 mL/min; tr major 15.6 min, minor 25.2 min). Colorless solids of mp

69–71 °C. [α]D20

+94 (c 0.52, CHCl3). 1H NMR: 1.25–1.39 (m, 2H), 1.44 (m, 1H), 1.56 (m, 1H),

1.77 (d, J = 12.0, 1H), 1.86–1.95 (m, 2H), 2.43 (m, 1H), 2.63 (m, 1H), 3.75 (m, 1H), 5.65 (d, J

= 9.2, 1H), 6.48 (d, J = 9.2, 1H), 7.06–7.13 (m, 3H), 7.18–7.23 (m, 2H), 7.26–7.33 (m, 3H), 7.34–7.38 (m, 2H),

7.38–7.44 (t, J = 7.9, 2H), 7.47–7.54 (m, 3H). 13C NMR: 24.85, 25.86, 32.13, 33.00, 50.51, 77.79, 79.38, 125.90,

126.01, 127.14, 127.98, 128.06, 128.13, 128.35, 131.80, 133.44, 140.29, 144.87, 166.84. IR (KBr): 2928, 1667,

1508, 1481, 1450, 1342, 1215, 1065. HRMS–ESI (m/z): [M + Na]+ calcd for C26H27NO2Na, 408.1934; found,

408.1938. The absolute configuration was assigned based on that of 4b.

��

6. Wang, L.; Akhani, R. K.; Wiskur, S. L. Org. Lett. 2015, 17, 2408.

Bn

Ph NHBz

O H

Ph

Ph NHBz

O H

Ph

Ph NHBz

O H


S4�

N-[(R)-((1R,2S)-2-tert-Butylcyclohexyloxy)(phenyl)methyl]benz-

amide (4c) and N-[(R)-((1S,2R)-2-tert-Butylcyclohexyloxy)(phenyl)-

methyl]benzamide (5c): Purified by column chromatography

(hexane/EtOAc 20:1). Colorless oil. 96% and 95% ee, respectively

(Daicel Chiralcel AD-H; 254 nm; hexane/i-PrOH 19:1, 0.8 mL/min: tr

4c major 10.3 min, minor 14.5 min; 5c major 8.6 min, minor 12.4 min). HRMS–ESI (m/z): [M + Na]+ calcd for

C24H31NO2Na, 388.2247; found, 388.2249. The diastereomers were separated by column chromatography

(hexane/EtOAc 20:1) and further characterized.

4c: 1H NMR: 0.90 (s, 9H), 1.06 (m, 1H), 1.16–1.26 (m, 2H), 1.35 (ddd, J = 11.0, 8.5, 4.0, 1H), 1.49 (m, 1H),

1.58–1.70 (m, 2H), 1.82 (m, 1H), 2.13 (m, 1H), 3.78 (ddd, J = 9.0, 9.0, 4.0, 1H), 6.58 (d, J = 9.0, 1H), 6.64 (d,

J = 9.0, 1H), 7.31 (m, 1H), 7.34–7.40 (m, 2H), 7.41–7.47 (m, 2H), 7.48–7.55 (m, 3H), 7.74–7.81 (m, 2H). 13C

NMR: 24.3, 25.5, 26.3, 29.4, 33.0, 34.0, 51.8, 80.4, 80.6, 126.1, 127.0, 128.2, 128.5, 128.7, 131.8, 134.1,

140.5, 166.3. IR (neat): 3305, 2924, 2862, 1639, 1519, 1485, 1365, 1269, 1060, 1029. The absolute

configuration was tentatively assigned by analogy.

5c: 1H NMR: 0.97 (m, 1H), 1.01 (s, 9H), 1.13–1.31 (m, 3H), 1.38 (ddd, J = 12.0, 9.0, 3.5, 1H), 1.63–1.77 (m,

2H), 1.85 (m, 1H), 2.40 (m, 1H), 3.77 (ddd, J = 9.5, 9.5, 4.0, 1H), 6.58 (d, J = 9.5, 1H), 6.73 (d, J = 9.5, 1H),

7.31 (t, J = 7.0, 1H), 7.37 (t, J = 7.5, 2H), 7.45 (t, J = 7.5, 2H), 7.49–7.57 (m, 3H), 7.79 (d, J = 8.5, 2H). 13C

NMR: 24.6, 26.1, 26.8, 29.5, 31.7, 33.2, 51.6, 76.4, 77.9, 126.1, 127.0, 128.1, 128.5, 128.7, 131.9, 133.9,

140.8, 167.3. IR (neat): 3279, 2928, 2858, 1728, 1643, 1523, 1486, 1338, 1273, 1064, 1034. The absolute

configuration was tentatively assigned by analogy.

Hydrolysis of 4a to (1R,2S)-1a: To a stirred solution of 4a (102 mg, 0.254 mmol) in a 4:1 mixture of EtOAc/H2O

(1.25 mL) was added (PhO)2PO3H (12.7 mg, 0.200 equiv) at rt. After 1 h, sat. aq. NaHCO3 was added to the

mixture, and the whole was extracted with EtOAc. The organic layer was dried over Na2SO4 and evaporated. The

resulting residue was purified by silica-gel flash chromatography (hexane/EtOAc 9:1 to 4:1) to give (1R,2S)-1a

(46.7 mg) in 97% yield as a colorless oil: [α]D30 –41.6 (c 1.00, CHCl3). The enantiomeric excess (99% ee) was

determined by chiral HPLC analysis (Daicel Chiralpak IC-3; 254 nm; hexane/i-PrOH 97:3, 1.0 mL/min; tr major

11.1 min, minor 13.3 min). The absolute configuration was determined by comparing the specific rotation to that

reported for the other enantiomer (vide infra).

(1S,2R)-1a: The above procedure using 5a (205 mg, 0.512 mmol) in place of 4a and (PhO)2PO3H (25.2 mg, 0.200

equiv) in a 4:1 mixture of EtOAc/H2O (2.5 mL) gave the title compound (89.3 mg) in 92% yield as a colorless oil:

[α]D30 +36.0 (c 1.13, CHCl3) The enantiomeric excess (94% ee) was determined by chiral HPLC analysis (Daicel

Chiralpak IC-3; 254 nm; hexane/i-PrOH 97:3, 1.0 mL/min; tr minor 11.2 min, major 13.3 min).. The absolute

configuration was determined by comparison of the specific rotation to that reported ([α]D20 +49.2 (c 1, CHCl3).7

��

7. (a) Fronza, G.; Fogliato, G.; Fuganti, C.; Lanati, S.; Rallo, R.; Servi, S. Tetrahedron Lett. 1995, 36, 121. (b) Fogliato, G.; Fronza, G.; Fuganti, C.; Lanati, S.; Rallo, R.; Rigoni, R.; Servi, S. Tetrahedron 1995, 51, 10231.

t-Bu

Ph NHBz

O

t-Bu

Ph NHBz

OH H+


S5�

1H NMR of 4a

Bn

Ph NHBz

O H


S6�

13C NMR of 4a

Bn

Ph NHBz

O H


S7�

HPLC of (±)-4a

HPLC of 4a


S8�

1H NMR of 5a

Bn

Ph NHBz

O H


S9�

13C NMR of 5a

Bn

Ph NHBz

O H


S10�

HPLC of (±)-5a

HPLC of 5a


S11�

1H NMR of 4b

Ph

Ph NHBz

O H


S12�

13C NMR of 4b

Ph

Ph NHBz

O H


S13�

1H NMR of 5b

Ph

Ph NHBz

O H


S14�

13C NMR of 5b

Ph

Ph NHBz

O H


S15�

HPLC of (±)-4b and (±)-5b

HPLC of 4b and 5b

4b

5b

ent-4b

ent-5b


S16�

1H NMR of 4c

t-Bu

Ph NHBz

O H


S17�

13C NMR of 4c

t-Bu

Ph NHBz

O H


S18�

1H NMR of 5c

t-Bu

Ph NHBz

O H


S19�

13C NMR of 5c

t-Bu

Ph NHBz

O H


S20�

HPLC of (±)-4c

HPLC of (±)-5c

HPLC of 4c and 5c


S21�

HPLC of (±)-1a

(1R,2S)-S1 with 99% ee

(1S,2R)-S1 with 94% ee

optical resolution via catalytic generation of chiral ... · s2 experimental section general. all...

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