SupportingInformation
Remarkable magnitude of the self-disproportionation of enantiomers (SDE) via achiral chromatography; application to the practical-scale enantiopurification of -amino acid esters
Alicja Wzorek,*ab Azusa Sato,cb Józef Drabowicz,de Vadim A. Soloshonok,*bf and Karel D. Klika*g
aInstitute of Chemistry
Jan Kochanowski University in Kielce
Świętokrzyska 15G, 25-406 Kielce (Poland)
bDepartment of Organic Chemistry I, Faculty of Chemistry
University of the Basque Country UPV/EHU
Paseo Manuel Lardizábal 3, 20018 San Sebastián (Spain)
cDepartment of Chemistry
Tokyo Women’s Medical University
8-1 Kawada-cho, Shinjuku-ku, 162-8666 Tokyo, (Japan)
dDepartment of Heteroorganic Chemistry, Center of Molecular and Macromolecular Studies
Polish Academy of Sciences
Sienkiewicza 112, 90-363 Łódź (Poland)
eInstitute of Chemistry, Environmental Protection and Biotechnology
Jan Długosz University in Czestochowa
Armii Krajowej 13/15, 42-201 Częstochowa (Poland)
fIKERBASQUE, Basque Foundation for Science
Alameda Urquijo 36-5
Plaza Bizkaia, 48011 Bilbao (Spain)
gMolecular Structure Analysis, German Cancer Research Center (DKFZ)
Im Neuenheimer Feld 280, D-69009 Heidelberg (Germany)
Emails: , ,
Table of contents
page
1. / Experimental...... / S22. / References...... / S6
3. / Fig.s S1–S12:Chromatograms of chiral HPLC of compounds 1–6...... / S7
4. / Fig.s S7–S24:1H and 13C NMR spectra of compounds 1–6...... / S10
5. / Fig.s S25–S44 and Tables S1–20:Graphical representation and tabulation of fractions of runs 1–20... / S16
General experimental.All chemical reagents used in this work were purchased from either Aldrich or Fluka. Lipase Amano PS immobilized on diatomite was purchased from Aldrich. Column chromatography solvents c-hexane, ethyl acetate (EtOAc), acetonitrile (ACN), toluene, and diethyl ether (Et2O) were purchased from Chempur (Poland) while methyl t-butyl ether (MTBE) was purchased fromAcros. HPLC solvents n-hexane and i-propanol and silica gel (230–400 mesh) for column chromatography were purchased from Merck. Aluminum oxide (neutral, grade I) for column chromatography was purchased from POCh (Poland). All solvents were used without further purification.
GC analysis was performed on a Thermo Scientific-Trace 1310 instrument equipped with a TG-5HT column (30 m 0.25 mm). Temperatures: injector, 300 C; detector (FID), 280 C; and column,from 150 to 350 C at 10 C/min.HPLC analysis was performed on a Varian ProStar instrument equipped with a UV-vis detector and a Vertex Plus Eurocel 01 chiral column (5 m, 250 4.6 mm) (Knauer, Germany) using n-hexane–i-propanol (90:10) as the mobile phase at a flow rate of 1.0–1.2 mL/min.Gravity-driven column chromatography with the various eluents and proportions of stationary phase given in the text was performed using a column of diameter 15 mm and height 500 mm. Samples were loaded onto the column as a solution in CH2Cl2–c-hexane and eluted with target flows of 3–5 min/10 mL amounting to total elution times of ca. 2–18 h.
General procedure for the synthesis of racemic -amino acids. Racemic -amino acids for derivatization to N-acetyl-amino acid ethyl esters 1–6were synthesized according to literature1 from appropriate aromatic aldehydes (5 mmol) by heating with malonic acid (2 equiv.) and NH4Ac (2 equiv.) in ethanol at reflux for 6–8 h. In all cases, the products precipitated directly from the reaction as white solids. Physical and spectral data were consistent with literature.2
General procedure for the synthesis of racemic N-acetyl -amino acid ethyl esters 1–6.2cTo a solution of 20 mL of absolute ethanol was added SOCl2 (9 mmol) at −10 C (ice–NaCl–methanol bath) with the appropriate -amino acid (7 mmol). The reaction mixture was stirred for 3 h at room temperature and then heated under reflux for 1 h. After cooling to room temperature, the solution was poured into a saturated NaCO3solution and extracted with ethyl acetate (3 20mL). The combined organic extracts were washed with brine, dried over MgSO4, and then evaporated to dryness. To the oily residue was added anhydrous THF (20 mL), NEt3 (10.5 mmol) and, after cooling to 0 C, acetyl chloride (7 mmol). The reaction mixture was stirred at room temperature for 5 h and was then poured into anaqueous saturated NH4Cl solution and extracted with ethyl acetate (3 20mL). The combined organic extracts were washed with brine, dried over MgSO4, and then evaporated to dryness. The crudeN-acetyl-amino acid ethyl esterwas purified via column chromatography using ethyl acetate–hexane (2:1, respectively) as eluent. Spectral data were consistent with literature.3
rac-Ethyl 3-acetamido-3-phenylpropanoate (1): wt, 0.72 g; yield, 46.4%; mp, 36–37 C; chiral HPLC: (R) t1, 12.8 min; (S) t2, 14.6 min; 1H NMR (600 MHz, CDCl3): (ppm): 1.17 (t, 3H, J=7.1Hz, CH3CH2O–), 2.01 (s, 3H, CH3CO), 2.82 (dd, 1H, Jgem= −15.5, Jvic=5.9 Hz, one of –CH2–), 2.92 (dd, 1H, Jgem= −15.5, Jvic= 6.0 Hz, one of –CH2–), 4.07 (qt, 2H, J=7.1 Hz, CH3CH2O–), 5.43 (qt, 1H, J=6.5 Hz, CH), 6.96 (d, 1H, J=6.6 Hz, NH), 7.25–7.35 (m, 5H, C6H5–); 13C NMR (ppm): 14.03, 23.22, 40.13, 49.87, 60.91, 126.43, 127.60, 128.73, 140.96, 169.77, 171.23; calcd for C13H17NO3: C 66.36, H 7.28, N 5.95; found: C 65.85, H 7.18, N 5.82.
rac-Ethyl 3-acetamido-3-phenyl-(4-methylphenyl)propanoate (2): wt, 0.94 g; yield, 57.3%; mp, 52–54 C; chiral HPLC: (R) t1, 12.6 min; (S) t2, 15.5 min;1H NMR (600 MHz, CDCl3): (ppm): 1.17 (t, 3H, J=7.1Hz, CH3CH2O–),2.01 (s, 3H, CH3CO),2.31 (s, 3H, CH3C6H4–),2.79 (dd, 1H, Jgem= −15.7, Jvic= 6.1 Hz, one of –CH2–), 2.90 (dd, 1H, Jgem= −15.7, Jvic= 6.1 Hz, one of –CH2–), 4.06 (qt, 2H, J=7.1 Hz, CH3CH2O–), 5.37 (qt, 1H, J= 6.3 Hz, CH), 6.83 (d, 1H, J= 5.3 Hz, NH), 7.11–7.13 (m, 2H, –C6H4–), 7.17–7.18 (m, 2H, –C6H4–); 13C NMR (ppm): 14.16, 21.14, 23.34, 40.09, 49.62, 60.84, 126.35, 129.45, 137.42, 137.59, 169.63, 171.36; calcd for C14H19NO3: C 67.45, H 7.68, N 5.62; found: C 67.19, H 7.55, N 5.58.
rac-Ethyl 3-acetamido-3-phenyl-(4-fluorophenyl)propanoate (3):wt, 0.98 g; yield, 58.7%; mp, 50–53 C; chiral HPLC: (R) t1, 10.8 min; (S) t2, 12.8 min;1H NMR (600 MHz, CDCl3): (ppm): 1.18 (t, 3H, J=7.1Hz, CH3CH2O–),2.02 (s, 3H, CH3CO),2.80 (dd, 1H, Jgem= −15.7, Jvic= 6.0 Hz, one of –CH2–), 2.89 (dd, 1H, Jgem= −15.7, Jvic= 6.1 Hz, one of –CH2–), 4.08 (qt, 2H, J=7.1 Hz, CH3CH2O–), 5.40 (qt, 1H, J= 6.5 Hz, CH), 6.99–7.02 (m, 3H,NH, –C6H4–), 7.27–7.29 (m, 2H, –C6H4–); 13C NMR (ppm): 14.10, 23.25, 40.14, 49.23, 60.92, 115.47, 128.11, 136.90, 161.30, 163.17, 169.80, 170.96;calcd for C13H16NO3F:C 61.65, H 6.37, N 5.53; found: C 61.51, H 6.32, N 5.44.
rac-Ethyl 3-acetamido-3-phenyl-(4-chlorophenyl)propanoate (4):wt, 1.12 g; yield, 63.0%; mp, 70–72 C; chiral HPLC: (R) t1, 11.1 min; (S) t2, 13.6 min;1H NMR (600 MHz, CDCl3):(ppm): 1.16 (t, 3H, J=7.1Hz, CH3CH2O–),2.01 (s, 3H, CH3CO),2.78 (dd, 1H, Jgem= −15.9, Jvic= 5.9 Hz, one of –CH2–), 2.87 (dd, 1H, Jgem= −15.8, Jvic= 6.0 Hz, one of –CH2–), 4.06 (qt, 2H, J=7.1 Hz, CH3CH2O–), 5.37 (qt, 1H, J= 6.1 Hz, CH), 7.00(d, 1H, J=4.7 Hz, NH), 7.21–7.23 (m, 2H, –C6H4–), 7.26–7.28 (m, 2H, –C6H4–);13C NMR (ppm): 14.14, 23.30, 39.89, 49.22, 61.02, 127.86, 128.88, 133.47, 139.22, 169.72, 171.16; calcd for C13H16NO3Cl: C 57.89, H 5.98, N 5.19; found: C 57.74, H 6.02, N 5.12.
rac-Ethyl 3-acetamido-3-phenyl-(4-methoxyphenyl)propanoate (5): wt, 0.90 g; yield, 51.4%; mp, 59–62 C; chiral HPLC: (R) t1, 15.6 min; (S) t2, 19.2 min;1H NMR (600 MHz, CDCl3): (ppm): 1.16 (t, 3H, J=7.1Hz, CH3CH2O–),2.00(s, 3H, CH3CO), 2.77 (dd, 1H, Jgem= −15.6, Jvic= 6.1 Hz, one of –CH2–), 2.89 (dd, 1H, Jgem= −15.6, Jvic= 6.0 Hz, one of –CH2–), 3.77 (s, 3H, CH3OC6H4–), 4.05 (qt, 2H, J=7.1 Hz, CH3CH2O–), 5.35 (qt, 1H, J= 6.6 Hz, CH), 6.83–6.84 (m, 3H,NH, –C6H4–), 7.20–7.21 (m, 2H, –C6H4–); 13C NMR (ppm):14.15, 23.30, 40.15, 49.39, 55.36, 60.82, 114.12, 127.67, 132.69, 159.08, 169.64, 171.33; calcd for C14H19NO4:C 63.38, H 7.22, N 5.28; found: C 62.86, H 7.14, N 5.18.
rac-Ethyl 3-acetamido-3-phenyl-benzo[1,3]dioxol-5-ylpropanoate (6):wt, 1.13 g; yield, 61.4%; mp, 102–104 C; chiral HPLC: (R) t1, 17.3 min; (S) t2, 20.8 min;1H NMR (600 MHz, CDCl3): (ppm): 1.18 (t, 3H, J=7.1Hz, CH3CH2O–),2.02 (s, 3H, CH3CO), 2.76 (dd, 1H, Jgem= −15.6, Jvic= 6.1 Hz, one of –CH2–), 2.87 (dd, 1H, Jgem= −15.6, Jvic= 6.0 Hz, one of –CH2–), 4.08 (qt, 2H, J=7.1 Hz, CH3CH2O–), 5.31 (qt, 1H,J= 6.6 Hz, CH), 5.92 (s, 2H, –O–CH2–O–), 6.73–6.79 (m, 3H, –C6H3–), 6.90 (d, J=3.7 Hz, NH);13C NMR (ppm): 14.14, 23.32, 40.22, 49.75, 60.98, 101.24, 107.10, 108.42, 119.73, 147.09, 148.01, 169.89, 171.29; calcd for C14H17NO5: C 60.21, H 6.14, N 5.15; found: C 60.21, H 6.16, N 4.94.
General procedure for the synthesis of (R)-N-acetyl -amino acid ethyl esters.2c Racemic -amino acid ethyl esters (3 mmol) obtained as described above were dissolved in i-Pr2O (25 mL). Next, Lipase Amano PS (0.75 g) and H2O (27 L, 1.5 mmol) was added and the reaction mixture stirred at 45 C for 18–24 h. The enzyme was filtered off and the solution evaporated to dryness. The residual (R)--amino acid ethyl esters were converted back into N-acetyl derivatives by reaction with acetyl chlorideas per above for the racemic derivatives. Spectral data were consistent with literature.3
(R)-Ethyl 3-acetamido-3-phenylpropanoate (1): ee, >99.9%; wt, 0.28 g; yield, 40.0%.
(R)-Ethyl 3-acetamido-3-(4-methylphenyl)propanoate (2): ee, 98.5%; wt, 0.15 g; yield, 20.0%.
(R)-Ethyl 3-acetamido-3-(4-fluorophenyl)propanoate (3): ee,79.8%; wt, 0.20 g; yield, 26.4%.
(R)-Ethyl 3-acetamido-3-(4-chlorophenyl)propanoate (4): ee,96.0%; wt, 0.17 g; yield, 21.0%.
(R)-Ethyl 3-acetamido-3-(4-methoxyphenyl)propanoate (5): ee, >99.9%; wt, 0.15 g; yield, 18.9%.
(R)-Ethyl 3-acetamido-3-phenyl-benzo[1,3]dioxol-5-ylpropanoate (6): ee >99.9%; wt, 0.17 g; yield, 20.3%.
Preparation of scalemic samples of compounds 1–6. Scalemates enriched in the R enantiomer for N-acetyl-amino acid ethyl esters 1–6were prepared by mixing enantiopure material and racemic material. The ees of the scalemates were determined by chiral HPLC.
1(ee, 69.2%).1H NMR (500 MHz, CDCl3): (ppm): 1.13 (t, 3H, J = 7.1 Hz, CH3CH2O–), 1.99 (s, 3H, CH3CO), 2.78 (dd, 1H, Jgem= −15.6, Jvic=5.9 Hz, one of –CH2–), 2.88 (dd, 1H, Jgem= −15.6, Jvic= 6.0 Hz, one of –CH2–), 4.03 (qt, 2H, J=7.1 Hz, CH3CH2O–), 5.40 (qt, 1H, J=6.5 Hz, CH), 6.63 (d, 1H, J= 7.0 Hz, NH), 7.22–7.31 (m, 5H, C6H5–).
2(ee, 74.0%); 1H NMR (500 MHz, CDCl3): (ppm): 1.17 (t, 3H, J=7.1Hz, CH3CH2O–),2.00 (s, 3H, CH3CO),2.32 (s, 3H, CH3C6H4–),2.78 (dd, 1H, Jgem= −15.6, Jvic= 5.9 Hz, one of –CH2–), 2.90 (dd, 1H, Jgem= −15.6, Jvic= 6.1 Hz, one of –CH2–), 4.07 (qt, 2H, J=7.1 Hz, CH3CH2O–), 5.38 (qt, 1H, J= 6.1 Hz, CH), 6.60 (d, 1H, J= 7.6 Hz, NH), 7.12–7.13 (m, 2H, –C6H4–), 7.17–7.19 (m, 2H, –C6H4–).
3(ee, 79.8%): 1H NMR (500 MHz, CDCl3): (ppm): 1.17 (t, 3H, J = 7.1 Hz, CH3CH2O–), 1.98 (s, 3H, CH3CO),2.79 (dd, 1H, Jgem= −15.7, Jvic= 6.0 Hz, one of –CH2–), 2.88 (dd, 1H, Jgem= −15.7, Jvic= 5.9 Hz, one of –CH2–), 4.07 (qt, 2H, J=7.1 Hz, CH3CH2O–), 5.39 (qt, 1H, J= 6.0 Hz, CH), 6.75 (d, 1H, J=7.5 Hz, NH), 6.98–7.02 (m, 2H, –C6H4–), 7.25–7.28 (m, 2H, –C6H4–).
4(ee, 71.7%): 1H NMR (500 MHz, CDCl3):(ppm): 1.17 (t, 3H, J=7.1Hz, CH3CH2O–),2.02 (s, 3H, CH3CO),2.80 (dd, 1H, Jgem= −15.8, Jvic= 5.8 Hz, one of –CH2–), 2.87 (dd, 1H, Jgem= −15.8, Jvic= 5.8 Hz, one of –CH2–), 4.07 (qt, 2H, J=7.1 Hz, CH3CH2O–), 5.38 (dt, 1H, J= 8.3, J= 5.8 Hz, CH), 6.74 (d, 1H, J= 7.9Hz, NH), 7.22–7.24 (m, 2H, –C6H4–), 7.29–7.30 (m, 2H, –C6H4–).
5(ee, 61.8%): 1H NMR (500 MHz, CDCl3): (ppm): 1.17 (t, 3H, J=7.1Hz, CH3CH2O–),2.00(s, 3H, CH3CO), 2.78 (dd, 1H, Jgem= −15.6, Jvic= 6.2 Hz, one of –CH2–), 2.90 (dd, 1H, Jgem= −15.6, Jvic= 5.9 Hz, one of –CH2–), 3.78 (s, 3H, CH3OC6H4–), 4.07 (qt, 2H, J=7.1 Hz, CH3CH2O–), 5.37 (qt, 1H, J=6.1 Hz, CH), 6.57 (d, 1H, J=7.7 Hz, NH), 6.84–6.86 (m, 3H,NH, –C6H4–), 7.20–7.22 (m, 2H, –C6H4–).
6(ee, 69.4%): 1H NMR (500 MHz, CDCl3): (ppm): 1.19 (t, 3H, J=7.1Hz, CH3CH2O–),2.02 (s, 3H, CH3CO), 2.77 (dd, 1H, Jgem= −15.6, Jvic= 6.0 Hz, one of –CH2–), 2.86 (dd, 1H, Jgem= −15.6, Jvic= 5.9 Hz, one of –CH2–), 4.08 (qt, 2H, J=7.1 Hz, CH3CH2O–), 5.31 (dt, 1H,J= 8.3, J= 6.0 Hz, CH), 5.93 (s, 2H, –O–CH2–O–), 6.60 (d, J=3.7 Hz, NH),6.72–6.80 (m, 3H, –C6H3–).
References
1.H. Kawasaki, K. Koyama, S. Kurokawa, K. Watanabe, M. Nakazawa, K. Izawa, T. Nakamatsu, Biosci. Biotechnol. Biochem.2006, 70, 99–106.
2.a) V. A. Soloshonok, N. A. Fokina, A. V. Rybakova, I. P. Shishkina, S.V. Galushko, A. E. Sorochinsky, V. P. Kukhar, M. V. Savchenko, V.K. Śvedas, Tetrahedron: Asymmetry1995, 6, 1601–1610; b) S. Fustero, M. Dolores Díaz, A. Navarro, E. Salavert, E. Aguilar, Tetrahedron2001, 57, 703–712; c) G. Tasnádi, E. Forró, F. Fülöp, Tetrahedron: Asymmetry2008, 19, 2072–2077.
3. a) S. Enthaler, G. Erre, K. Junge, K. Schröder, D. Addis, D. Michalik, M. Hapke, D. Redkin, M. Beller, Eur. J. Org. Chem. 2008, 3352–3362; b)D. Peňa, A. J. Minnaard, J. G. de Vries, B. L. Feringa, J. Am. Chem. Soc.2002, 124, 14552–14553; c) Y.-G. Zhou, W. Tang, W.-B. Wang, W. Li, X. Zhang, J. Am. Chem. Soc.2002, 124, 4952–4953; d) J. You, H.-J. Drexler, S. Zhang, C. Fischer, D. Heller, Angew. Chem., Int. Ed.2003, 42, 913–915.
Fig. S1:Chiral HPLC of racemic ethyl 3-acetamido-3-phenylpropanoate (1).
Fig. S2:Chiral HPLC of (R)-ethyl 3-acetamido-3-phenylpropanoate (1).
Fig. S3:Chiral HPLC of racemic ethyl 3-acetamido-3-(4-methylphenyl)propanoate (2).
Fig. S4:Chiral HPLC of (R)-ethyl 3-acetamido-3-(4-methylphenyl)propanoate (2).
Fig. S5:Chiral HPLC of racemic ethyl 3-acetamido-3-(4-fluorophenyl)propanoate (3).
Fig. S6:Chiral HPLC of (R)-ethyl 3-acetamido-3-(4-fluorophenyl)propanoate (3).
Fig. S7:Chiral HPLC of racemic ethyl 3-acetamido-3-(4-chlorophenyl)propanoate (4).
Fig. S8:Chiral HPLC of (R)-ethyl 3-acetamido-3-(4-chlorophenyl)propanoate (4).
Fig. S9:Chiral HPLC of racemic ethyl 3-acetamido-3-(4-methoxyphenyl)propanoate (5).
Fig. S10:Chiral HPLC of (R)-ethyl 3-acetamido-3-(4-methoxyphenyl)propanoate (5).
Fig. S11:Chiral HPLC of racemic ethyl 3-acetamido-3-phenyl-benzo[1,3]dioxol-5-ylpropanoate (6).
Fig. S12:Chiral HPLC of (R)-ethyl 3-acetamido-3-phenyl-benzo[1,3]dioxol-5-ylpropanoate (6).
Fig. S13:1H NMR spectrum of ethyl 3-acetamido-3-phenylpropanoate (1).
Fig. S14:13C NMR spectrum of ethyl 3-acetamido-3-phenylpropanoate (1).
Fig. S15:1H NMR spectrum of ethyl 3-acetamido-3-(4-methylphenyl)propanoate (2).
Fig. S16:13C NMR spectrum of ethyl 3-acetamido-3-(4-methylphenyl)propanoate (2).
Fig. S17:1H NMR spectrum of ethyl 3-acetamido-3-(4-fluorophenyl)propanoate (3).
Fig. S18:13C NMR spectrum of ethyl 3-acetamido-3-(4-fluorophenyl)propanoate (3).
Fig. S19:1H NMR spectrum of ethyl 3-acetamido-3-(4-chlorophenyl)propanoate (4).
Fig. S20:13C NMR spectrum of ethyl 3-acetamido-3-(4-chlorophenyl)propanoate (4).
Fig. S21:1H NMR spectrum of ethyl 3-acetamido-3-(4-methoxyphenyl)propanoate (5).
Fig. S22:13C NMR spectrum of ethyl 3-acetamido-3-(4-methoxyphenyl)propanoate (5).
Fig. S23:1H NMR spectrum of ethyl 3-acetamido-3-phenyl-benzo[1,3]dioxol-5-ylpropanoate (6).
Fig. S24:13C NMR spectrum of ethyl 3-acetamido-3-phenyl-benzo[1,3]dioxol-5-ylpropanoate (6).
Fig. S25:Graphical representation of run 1 (see Table 1)for compound 1showing the % ee of each fraction vs. the weight percent of each fraction. The starting eeof 66.6% forthe 109.9 mg loaded onto the column is indicated. c-Hexane–EtOAc (2:1, respectively) was used as the eluent and the proportion of silica gel (230–400 mesh) to 1 was ca. 30 g per 1 mmol. The column flow rate was targeted to 6 min/10 mL and altogether 13 fractions were collected consisting of 9 10 mL early aliquots followed bya further 4 50 mL aliquots to give total a elution volume of 290 mL accumulated over the course of 6.8 h. The ees of each collected fraction are listed below in Table S1. The ee was 48.8%.
Table S1: Tabulation of the collected fractions for run 1for compound 1
Volume of fraction collected[mL] / ee
[%] / Weight
[mg] / Weight
[%]
1. / 10 / 75.4 / 2.1 / 1.9
2. / 10 / 49.6 / 2.4 / 2.2
3. / 10 / 56.2 / 2.8 / 2.6
4. / 10 / 66.4 / 3.3 / 3.0
5. / 10 / 63.0 / 4.0 / 3.6
6. / 10 / 61.2 / 5.4 / 4.9
7. / 10 / 63.6 / 5.7 / 5.2
8. / 10 / 68.6 / 6.1 / 5.6
9. / 10 / 65.8 / 6.3 / 5.7
10. / 50 / 68.0 / 29.1 / 26.5
11. / 50 / 61.4 / 21.9 / 19.9
12. / 50 / 48.2 / 13.0 / 11.8
13. / 50 / 26.6 / 7.8 / 7.1
Fig. S26:Graphical representation of run 2 (see Table 1)for compound 1showing the % ee of each fraction vs. the weight percent of each fraction. The starting eeof 66.6% forthe 100.9 mg loaded onto the column is indicated. c-Hexane–EtOAc (1:1) was used as the eluent and the proportion of silica gel (230–400 mesh) to 1 was ca. 30 g per 1 mmol. The column flow rate was targeted to 6 min/10 mL and altogether 13 10 mL fractionswere collected to give total a elution volume of 130 mL accumulated over the course of 2.8 h. The ees of each collected fraction are listed below in Table S2. The ee was 27.4%.
Table S2: Tabulation of the collected fractions for run 2for compound 1
Volume of fraction collected[mL] / ee
[%] / Weight
[mg] / Weight
[%]
1. / 10 / 71.2 / 7.1 / 7.0
2. / 10 / 71.2 / 14.3 / 14.2
3. / 10 / 66.2 / 14.2 / 14.1
4. / 10 / 69.0 / 13.0 / 12.9
5. / 10 / 63.8 / 12.5 / 12.4
6. / 10 / 64.8 / 10.5 / 10.4
7. / 10 / 63.8 / 8.5 / 8.4
8. / 10 / 57.4 / 7.0 / 6.9
9. / 10 / 63.0 / 4.7 / 4.7
10. / 10 / 61.6 / 3.6 / 3.6
11. / 10 / 60.2 / 2.3 / 2.3
12. / 10 / 64.4 / 1.8 / 1.8
13. / 10 / 43.8 / 1.4 / 1.4
Fig. S27:Graphical representation of run 3 (see Table 1)for compound 1showing the % ee of each fraction vs. the weight percent of each fraction. The starting eeof 61.0% forthe 93.9 mg loaded onto the column is indicated. MTBE–c-hexane (2:1) was used as the eluent and the proportion of silica gel (230–400 mesh) to 1 was ca. 30 g per 1 mmol. The column flow rate was targeted to 6 min/10 mL and altogether 15 fractions were collected consisting of 10 10 mL early aliquots followed bya further 5 50 mL aliquots to give total a elution volume of 350 mL accumulated over the course of 5.3 h. The ees of each collected fraction are listed below in Table S3. The ee was 55.5% and the yield was 3.5%.
Table S3: Tabulation of the collected fractions for run 3for compound 1
Volume of fraction collected[mL] / ee
[%] / Weight
[mg] / Weight
[%]
1. / 10 / >99.9 / 3.3 / 3.5
2. / 10 / 89.2 / 7.7 / 8.2
3. / 10 / 82.2 / 7.9 / 8.4
4. / 10 / 79.2 / 8.1 / 8.6
5. / 10 / 72.4 / 6.6 / 7.0
6. / 10 / 69.4 / 5.7 / 6.1
7. / 10 / 65.8 / 5.2 / 5.5
8. / 10 / 62.0 / 4.9 / 5.2
9. / 10 / 66.0 / 4.1 / 4.4
10. / 10 / 59.2 / 3.8 / 4.0
11. / 50 / 58.0 / 16.5 / 17.6
12. / 50 / 52.6 / 7.7 / 8.2
13. / 50 / 52.6 / 5.5 / 5.9
14. / 50 / 44.4 / 3.7 / 3.9
15. / 50 / 49.8 / 3.2 / 3.4
Fig. S28:Graphical representation of run 4 (see Table 1)for compound 1showing the % ee of each fraction vs. the weight percent of each fraction. The starting eeof 71.6% forthe 95.7 mg loaded onto the column is indicated. MTBE–c-hexane (2:1) was used as the eluent and the proportion of silica gel (230–400 mesh) to 1 was ca. 30 g per 1 mmol. The column flow rate was targeted to 6 min/10 mL and altogether 16 fractions were collected consisting of 10 10 mL early aliquots followed bya further 6 50 mL aliquots to give total a elution volume of 400 mL accumulated over the course of 5.3 h. The ees of each collected fraction are listed below in Table S4. The ee was 49.3% and the yield was 7.9%.
Table S4: Tabulation of the collected fractions for run4for compound 1
Volume of fraction collected[mL] / ee
[%] / Weight
[mg] / Weight
[%]
1. / 10 / >99.9 / 1.7 / 1.8
2. / 10 / >99.9 / 5.8 / 6.1
3. / 10 / 95.0 / 8.1 / 8.5
4. / 10 / 87.0 / 7.9 / 8.3
5. / 10 / 86.8 / 7.1 / 7.4
6. / 10 / 81.0 / 6.3 / 6.6
7. / 10 / 78.0 / 6.2 / 6.5
8. / 10 / 72.8 / 4.8 / 5.0
9. / 10 / 74.8 / 4.9 / 5.1
10. / 10 / 74.8 / 3.9 / 4.1
11. / 50 / 69.6 / 14.3 / 14.9
12. / 50 / 65.8 / 8.7 / 9.1
13. / 50 / 60.2 / 7.1 / 7.4
14. / 50 / 65.3 / 3.9 / 4.1
15. / 50 / 57.8 / 3.1 / 3.2
16. / 50 / 50.6 / 1.9 / 2.0
Fig. S29:Graphical representation of run 5 (see Table 1)for compound 1showing the % ee of each fraction vs. the weight percent of each fraction. The starting eeof 69.4% forthe 95.6 mg loaded onto the column is indicated. Et2O–c-hexane (4:1) was used as the eluent and the proportion of silica gel (230–400 mesh) to 1 was ca. 30 g per 1 mmol. The column flow rate was targeted to 5 min/10 mL and altogether 15 fractions were collected consisting of 10 10 mL early aliquots followed bya further 5 50 mL aliquots to give total a elution volume of 350 mL accumulated over the course of 5.5 h. The ees of each collected fraction are listed below in Table S5. The ee was 52.6%.
Table S5: Tabulation of the collected fractions for run 5for compound 1
Volume of fraction collected[mL] / ee
[%] / Weight
[mg] / Weight
[%]
1. / 10 / 97.0 / 3.2 / 3.4
2. / 10 / 92.4 / 5.6 / 5.9
3. / 10 / 90.4 / 7.5 / 7.8
4. / 10 / 85.2 / 8.2 / 8.6
5. / 10 / 80.0 / 8.0 / 8.4
6. / 10 / 76.2 / 8.0 / 8.4
7. / 10 / 74.4 / 6.6 / 6.9
8. / 10 / 67.8 / 6.4 / 6.7
9. / 10 / 69.4 / 4.8 / 5.0
10. / 10 / 64.6 / 5.2 / 5.4
11. / 50 / 61.2 / 17.0 / 17.8
12. / 50 / 56.4 / 7.0 / 7.3
13. / 50 / 49.6 / 5.2 / 5.4
14. / 50 / 44.4 / 1.9 / 2.0
15. / 50 / 49.0 / 1.0 / 1.0
Fig. S30:Graphical representation of run 6 (see Table 1)for compound 1showing the % ee of each fraction vs. the weight percent of each fraction. The starting eeof 69.4% forthe 98.3 mg loaded onto the column is indicated. Toluene–ACN (10:1) was used as the eluent and the proportion of silica gel (230–400 mesh) to 1 was ca. 30 g per 1 mmol. The column flow rate was targeted to 8 min/10 mL and altogether 18 fractions were collected consisting of 10 10 mL early aliquots followed bya further 8 50 mL aliquots to give total a elution volume of 500 mLaccumulated over the course of 12.7 h. The ees of each collected fraction are listed below in Table S6. The ee was 22.2%.
Table S6: Tabulation of the collected fractions for run 6for compound 1
Volume of fraction collected[mL] / ee
[%] / Weight
[mg] / Weight
[%]
1. / 10 / 68.8 / 1.2 / 1.2
2. / 10 / 71.8 / 2.2 / 2.2
3. / 10 / 71.2 / 3.3 / 3.4
4. / 10 / 73.0 / 3.1 / 3.2
5. / 10 / 63.0 / 3.3 / 3.4
6. / 10 / 69.0 / 3.0 / 3.0
7. / 10 / 73.6 / 2.8 / 2.8
8. / 10 / 73.6 / 2.9 / 3.0
9. / 10 / 70.4 / 3.2 / 3.3
10. / 10 / 84.0 / 3.7 / 3.8
11. / 50 / 73.2 / 24.5 / 24.9
12. / 50 / 74.0 / 11.2 / 11.4
13. / 50 / 73.0 / 7.1 / 7.2
14. / 50 / 71.8 / 6.6 / 6.7
15. / 50 / 78.2 / 6.6 / 6.7
16. / 50 / 66.8 / 5.4 / 5.5
17. / 50 / 64.2 / 5.2 / 5.3
18. / 50 / 61.8 / 3.0 / 3.0
Fig. S31:Graphical representation of run 7 (see Table 1)for compound 1showing the % ee of each fraction vs. the weight percent of each fraction. The starting eeof 71.6% forthe 104.5 mg loaded onto the column is indicated. Toluene–ACN (5:1) was used as the eluent and the proportion of silica gel (230–400 mesh) to 1 was ca. 30 g per 1 mmol. The column flow rate was targeted to 7 min/10 mL and altogether 12 10 mL fractions were collected to give total a elution volume of 120 mL accumulated over the course of 3.4 h. The ees of each collected fraction are listed below in Table S7. The ee was 9.2%.
Table S7: Tabulation of the collected fractions for run 7for compound 1
Volume of fraction collected[mL] / ee
[%] / Weight
[mg] / Weight
[%]
1. / 10 / 74.6 / 3.7 / 3.5
2. / 10 / 72.8 / 11.0 / 10.5
3. / 10 / 72.6 / 15.3 / 14.6
4. / 10 / 71.4 / 15.9 / 15.2
5. / 10 / 69.0 / 13.3 / 12.7
6. / 10 / 69.6 / 14.4 / 13.8
7. / 10 / 71.4 / 9.5 / 9.1
8. / 10 / 71.2 / 6.6 / 6.3
9. / 10 / 67.0 / 5.4 / 5.2
10. / 10 / 68.0 / 4.2 / 4.0
11. / 10 / 70.2 / 3.2 / 3.1
12. / 10 / 65.4 / 2.0 / 1.9
Fig. S32:Graphical representation of run 8 (see Table 2)for compound 1showing the % ee of each fraction vs. the weight percent of each fraction. The starting eeof 69.4% forthe 105.7 mg loaded onto the column is indicated. MTBE–c-hexane (2:1) was used as the eluent and the proportion of silica gel (230–400 mesh) to 1 was ca. 40 g per 1 mmol. The column flow rate was targeted to 9 min/10 mL and altogether 23 fractions were collected consisting of 10 10 mL early aliquots followed bya further 13 50 mL aliquots to give total a elution volume of 750 mL accumulated over the course of 16.6 h. The ees of each collected fraction are listed below in Table S8. The ee was 66.7%and the yield was 21.7%.
Table S8: Tabulation of the collected fractions for run 8for compound 1
Volume of fraction collected[mL] / ee
[%] / Weight
[mg] / Weight
[%]
1. / 10 / >99.9 / 1.5 / 1.4
2. / 10 / >99.9 / 2.5 / 2.4
3. / 10 / >99.9 / 3.6 / 3.4
4. / 10 / >99.9 / 3.8 / 3.6
5. / 10 / >99.9 / 3.9 / 3.7
6. / 10 / >99.9 / 4.1 / 3.9
7. / 10 / >99.9 / 3.5 / 3.3
8. / 10 / 93.4 / 3.8 / 3.6
9. / 10 / 92.4 / 2.8 / 2.6
10. / 10 / 89.8 / 2.8 / 2.6
11. / 50 / 81.6 / 14.1 / 13.3
12. / 50 / 70.4 / 10.2 / 9.6
13. / 50 / 67.8 / 7.2 / 6.8
14. / 50 / 61.4 / 6.9 / 6.5
15. / 50 / 59.0 / 5.8 / 5.5
16. / 50 / 53.0 / 4.6 / 4.4
17. / 50 / 50.8 / 3.7 / 3.5
18. / 50 / 47.4 / 3.6 / 3.4
19. / 50 / 44.2 / 3.5 / 3.3
20. / 50 / 37.8 / 6.4 / 6.1
21 / 50 / 34.6 / 3.9 / 3.7
22. / 50 / 33.2 / 2.3 / 2.2
23. / 50 / 39.4 / 1.2 / 1.1
Fig. S33:Graphical representation of run 9 (see Table 2)for compound 1showing the % ee of each fraction vs. the weight percent of each fraction. The starting eeof 70.2% forthe 115.1 mg loaded onto the column is indicated. c-Hexane–EtOAc (1:1) was used as the eluent and the proportion of silica gel (230–400 mesh) to 1 was ca. 50 g per 1 mmol. The column flow rate was targeted to 4 min/10 mL and altogether 16 fractions were collected consisting of 15 10 mL early aliquots followed bya further 50 mL aliquot to give total a elution volume of 200 mL accumulated over the course of 3.5 h. The ees of each collected fraction are listed below in Table S9. The ee was 36.0%.
Table S9: Tabulation of the collected fractions for run 9for compound 1
Volume of fraction collected[mL] / ee
[%] / Weight
[mg] / Weight
[%]
1. / 10 / 92.2 / 0.9 / 0.8
2. / 10 / 78.8 / 3.5 / 3.0
3. / 10 / 85.2 / 6.3 / 5.5
4. / 10 / 81.8 / 7.6 / 6.6
5. / 10 / 82.0 / 8.8 / 7.6
6. / 10 / 71.8 / 9.8 / 8.5
7. / 10 / 70.0 / 10.5 / 9.1
8. / 10 / 72.4 / 10.3 / 9.0
9. / 10 / 71.6 / 9.0 / 7.8
10. / 10 / 70.0 / 8.5 / 7.4
11. / 10 / 65.2 / 7.0 / 6.1
12. / 10 / 57.4 / 6.6 / 5.7
13. / 10 / 60.0 / 6.5 / 5.6
14. / 10 / 58.8 / 5.9 / 5.1
15. / 10 / 56.2 / 5.0 / 4.3
16. / 50 / 79.2 / 8.9 / 7.7
Fig. S34:Graphical representation of run 10 (see Table 2)for compound 1showing the % ee of each fraction vs. the weight percent of each fraction. The starting eeof 70.2% forthe 108.2 mg loaded onto the column is indicated. c-Hexane–EtOAc (2:1) was used as the eluent and the proportion of silica gel (230–400 mesh) to 1 was ca. 50 g per 1 mmol. The column flow rate was targeted to 4 min/10 mL and altogether 11 10 mL fractions were collected to give total a elution volume of 110 mL accumulated over the course of 1.7 h. The ees of each collected fraction are listed below in Table S10. The ee was 38.3%.
Table S10: Tabulation of the collected fractions for run 10for compound 1
Volume of fraction collected[mL] / ee
[%] / Weight
[mg] / Weight
[%]
1. / 10 / 86.7 / 0.6 / 0.6
2. / 10 / 81.6 / 8.8 / 8.1
3. / 10 / 78.8 / 18.4 / 17.0
4. / 10 / 79.0 / 20.9 / 19.3
5. / 10 / 75.8 / 19.3 / 17.8
6. / 10 / 70.4 / 14.8 / 13.7
7. / 10 / 70.8 / 10.3 / 9.5
8. / 10 / 64.4 / 6.8 / 6.3
9. / 10 / 54.0 / 4.7 / 4.3
10. / 10 / 64.8 / 2.6 / 2.4
11. / 10 / 48.4 / 1.0 / 0.9
Fig. S35:Graphical representation of run 11 (see Table 2)for compound 1showing the % ee of each fraction vs. the weight percent of each fraction. The starting eeof 69.0% forthe 94.4 mg loaded onto the column is indicated. MTBE was used as the eluent and the proportion of silica gel (230–400 mesh) to 1 was ca. 50 g per 1 mmol. The column flow rate was targeted to 6 min/10 mL and altogether 13 10 mL fractions were collected to give total a elution volume of 130 mL accumulated over the course of 2.6 h. The ees of each collected fraction are listed below in Table S11. The ee was 33.4%.
Table S11: Tabulation of the collected fractions for run 11for compound 1
Volume of fraction collected[mL] / ee
[%] / Weight
[mg] / Weight
[%]
1. / 10 / 86.0 / 6.5 / 6.9
2. / 10 / 83.0 / 17.6 / 18.6
3. / 10 / 73.6 / 19.5 / 20.7
4. / 10 / 70.6 / 14.5 / 15.4
5. / 10 / 67.6 / 10.0 / 10.6
6. / 10 / 63.0 / 7.4 / 7.8
7. / 10 / 64.8 / 6.1 / 6.5
8. / 10 / 65.8 / 3.8 / 4.0
9. / 10 / 63.4 / 2.8 / 3.0
10. / 10 / 57.2 / 2.3 / 2.4
11. / 10 / 55.6 / 1.6 / 1.7
12. / 10 / 52.6 / 1.3 / 1.4
13. / 10 / 52.8 / 1.0 / 1.1
Fig. S36:Graphical representation of run 12 (see Table 2)for compound 1showing the % ee of each fraction vs. the weight percent of each fraction. The starting eeof 74.0% forthe 58.8 mg loaded onto the column is indicated. MTBE was used as the eluent and the proportion of silica gel (230–400 mesh) to 1 was ca. 100 g per 1 mmol. The column flow rate was targeted to 6 min/10 mL and altogether 14 10 mL fractions were collected to give total a elution volume of 140 mL accumulated over the course of 3.1 h. The ees of each collected fraction are listed below in Table S12. The ee was 62.2%.
Table S12: Tabulation of the collected fractions for run 12for compound 1
Volume of fraction collected[mL] / ee
[%] / Weight
[mg] / Weight
[%]
1. / 10 / 94.0 / 9.4 / 16.0
2. / 10 / 80.2 / 17.8 / 30.3
3. / 10 / 69.2 / 14.4 / 24.5
4. / 10 / 64.8 / 7.2 / 12.2
5. / 10 / 61.6 / 4.4 / 7.5
6. / 10 / 57.0 / 2.5 / 4.2
7. / 10 / 53.6 / 0.9 / 1.5
8. / 10 / 47.6 / 0.7 / 1.2
9. / 10 / 51.0 / 0.5 / 0.8
10. / 10 / 48.0 / 0.4 / 0.7
11. / 10 / 38.0 / 0.2 / 0.3
12. / 10 / 38.4 / 0.2 / 0.3
13. / 10 / 33.6 / 0.1 / 0.2
14. / 10 / 31.8 / 0.1 / 0.2
Fig. S37:Graphical representation of run 13 (see Table 3)for compound 1showing the % ee of each fraction vs. the weight percent of each fraction. The starting eeof 73.0% forthe 112.4 mg loaded onto the column is indicated. c-Hexane–EtOAc (2:1) was used as the eluent and the proportion of aluminum oxide(neutral, grade I) to 1 was ca. 30 g per 1 mmol. The column flow rate was targeted to 7 min/10 mL and altogether 9 10 mL fractions were collected to give total a elution volume of 90 mL accumulated over the course of 1.8 h. The ees of each collected fraction are listed below in Table S13. The ee was −7.8%.
Table S13: Tabulation of the collected fractions for run 13for compound 1