K. A. J˘rgensen et al.
FULL PAPER
General procedure for catalytic enantioselective reaction of imines 1a f
with silylketene acetals: To a flame-dried Schlenk tube equipped with a
magnetic stirring bar was added Zn(OTf)2 (7.3 mg, 0.020 mmol), which
was gently dried with a heat-gun under vacuum. After cooling to room
temperature, (R)-Ph-pybox (8.1 mg, 0.022 mmol) was added and stirred
for an additional 1 h under vacuum. Wet CH2Cl2 (0.22 mL, H2O:
1660 ppm) was added and stirring continued for 1 h at ambient tempera-
ture followed by addition of imine (1.0 mL, 0.2m in CH2Cl2). After an ad-
ditional 30 min of stirring the solution was cooled to À788C. At that tem-
perature a solution of the silylketene acetal (1.2 equiv in 1 mL CH2Cl2)
was added drop wise over the course of 2 h and subsequently quenched
with H2O (0.2 mL) after 2.5 h. The reaction mixture was left to warm to
room temperature and filtered through a plug of silica gel (15 cm silica
gel, eluent: 50 mL 30% Et2O in CH2Cl2), concentrated in vacuo and pu-
rified by FC.
7.3 Hz, 1H; CH), 1.15 (t, J=7.3, 3H; CH3), 1.05 ppm (d, J=7.7 Hz, 3H;
CH3); 13C NMR (100 MHz, CDCl3): d=175.2, 171.1, 149.8, 149.2, 130.6,
124.9, 124.6, 117.3, 115.5, 65.4, 62.9, 52.6, 46.5, 13.8, 11.7 ppm; [a]RDT =+
78 (c=1.0 in CHCl3), (52%ee); HRMSC 15H17NO6 [M+Na]+ ; calcd:
330.0954, found: 330.0949.
anti-7 f: The ee was determined by HPLC using a Daicel Chiralcel OD
column (hexane/iPrOH (90/10); flow rate 1.0 mLminÀ1; tmajor =14.6 min;
tminor =30.3 min). 1H NMR (400 MHz, CDCl3): d=7.43 (d, J=8.0 Hz,
1H; ArH), 7.31 (t, J=8.0 Hz, 1H; ArH), 7.14 (t, J=7.3 Hz, 1H; ArH),
7.01 (d, J=7.3, 1H; ArH), 5.83 (s, 1H; NH), 4.14 4.40 (m, 4H; CH,
OCHH, OCH2), 4.07 (dd, J=8.8, 12.8 Hz, 1H; OCHH), 2.11 (m, 1H;
CHH), 1.96 (m, 1H; CHH), 1.23 ppm (t, J=7.0 Hz, 3H; OCH2CH3); 13C
NMR (100 MHz, CDCl3): d=174.8, 169.7, 149.0, 148.9, 130.8, 125.3,
125.1, 117.2, 115.5, 66.8, 63.4, 49.4, 24.1, 13.8 ppm; [a]RDT =+122 (c=1.0
in CHCl3), (95% ee); HRMSC 15H15NO6 [M+Na]+ ; calcd: 328.0797,
found: 328.0812
7a: The ee was determined by HPLC using a Daicel Chiralcel OD
column (hexane/iPrOH (90/10); flow rate 1.0 mLminÀ1; tmajor =8.2 min;
tminor =10.5 min). 1H NMR (400 MHz, CDCl3): d=7.42 (d, J=8.0 Hz,
1H; ArH), 7.36 (t, J=7.7 Hz, 1H; ArH), 7.13 (t, J=7.8 Hz, 1H; ArH),
6.98 (d, J=8.2 Hz, 1H; ArH), 6.50 (s, 1H; NH), 4.30 4.13 (m, 2H;
OCH2), 3.71 (s, 3H; OCH3), 1.47 (s, 3H; CH3), 1.25 (dt, J=1.6, 7.1 Hz,
3H; CH2CH3), 1.17 ppm (s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=
176.8, 169.6, 150.2, 149.4, 130.5, 127.7, 123.8, 117.1, 114.4, 67.6, 62.6, 53.5,
52.6, 22.7, 22.2, 13.8 ppm; [a]RDT =+118 (c=1.0 in CHCl3), (95% ee);
HRMSC 16H19NO6 [M+Na]+ ; calcd: 344.1110, found: 344.1122.
syn-7 f: The ee was determined by HPLC using a Daicel Chiralcel OD
column (hexane/iPrOH (70/30); flow rate 1.0 mLminÀ1; tmajor =18.8 min;
tminor =23.3 min). 1H NMR (400 MHz, CDCl3): d=7.62 (s, 1H; NH),
7.28 7.38 (m, 2H; ArH, 7.11 (t, J=8.1 Hz, 1H; ArH), 7.04 (d, J=8.4 Hz,
1H; ArH), 4.34 (t, J=9.2 Hz, 1H; OCHH), 4.08 4.30 (m, 3H; OCH2,
CH), 3.41 (dd, J=9.2, 11.4 Hz, 1H; OCHH), 2.52 (m, 1H; CHH), 2.29
(m, 1H; CHH), 1.22 ppm (t, J=7.0 Hz, 3H; OCH2CH3); 13C NMR
(100 MHz, CDCl3): d=174.9, 169.0, 149.4, 149.3, 130.7, 125.5, 124.8,
117.2, 115.8, 66.3, 63.6, 63.4, 49.7, 25.1, 13.9 ppm; [a]RDT =+60 (c=1.0 in
CHCl3), (85% ee); HRMSC 15H15NO6 [M+Na]+ ; calcd: 328.0797, found:
328.0796.
7b: The ee was determined by HPLC using a Daicel Chiralcel OD
column (hexane/iPrOH (90/10); flow rate 1.0 mLminÀ1; tmajor =6.8 min;
tminor =8.3 min). 1H NMR (400 MHz, CDCl3): d=7.41 (d, J=8.0 Hz, 1H;
ArH), 7.35 (t, J=7.8 Hz, 1H; ArH), 7.12 (t, J=7.7 Hz, 1H; ArH), 7.08
(d, J=8.1 Hz, 1H; ArH), 6.49 (s, 1H; NH), 4.28 4.10 (m, 4H; 2î
(OCH2)), 1.47 (s, 3H; CH3), 1.29 1.24 (m, 6H; 2î(CH2CH3)), 1.16 ppm
(s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=176.3, 169.7, 150.2, 149.4,
130.4, 127.6, 123.7, 117.0, 114.5, 67.6, 62.5, 61.6, 53.4, 22.7, 22.2, 13.9,
13.8 ppm; [a]RDT =+111 (c=1.0 in CHCl3), (94% ee); HRMSC 17H21NO6
[M+Na]+ ; calcd: 358.1267, found: 358.1258.
7 g: The ee was determined by HPLC using a Daicel Chiralcel OJ
column (hexane/iPrOH (70/30); flow rate 1.0 mLminÀ1; tmajor =15.8 min;
tminor =23.0 min). 1H NMR (400 MHz, CDCl3): d=7.39 (d, J=7.7 Hz,
1H; ArH), 7.30 (t, J=7.0 Hz, 1H; ArH), 7.10 7.15 (m, 2H; ArH and
NH), 7.00 (d, J=5.4 Hz, 1H; ArH), 5.26 (s, 1H; CH), 4.15 (m, 2H;
OCH2), 3.20 (d, J=15.0 Hz, 1H; CHH), 3.08 (d, J=15.0 Hz; CHH), 1.40
(s, 6H; 2î(CH3)), 1.18 ppm (t, J=7.0 Hz, 3H; OCH2CH3); 13C NMR
(100 MHz, CDCl3): d=169.8, 165.0, 160.2, 149.6, 148.9, 130.69, 126.0,
124.7, 116.9, 116.7, 106.9, 97.6, 63.2, 62.3, 42.0, 24.8, 24.2, 13.8 ppm;
7c: The ee was determined by HPLC using a Daicel Chiralcel OD
column (hexane/iPrOH (95/5); flow rate 1.0 mLminÀ1; tmajor =39.5 min;
[a]RDT =+61 (c=1.0 in CHCl3), (88% ee); HRMSC 18H19NO7 [M+Na]+
;
1
calcd: 384.1059, found: 358.1053.
tminor =54.5 min). H NMR (400 MHz, CDCl3) d 7.24 7.32 (m, 2H; ArH),
7.08 (t, J=7.3 Hz, 1H; ArH), 7.00 (d, J=8.8 Hz, 1H; ArH), 6.58 (s, 1H;
NH), 4.04 4.22 (m, 4H; 2î(OCH2)), 3.59 (d, J=17.2 Hz, 1H; CH2), 2.79
(d, J=17.2 Hz, 1H; CH2), 1.21 (t, J=7.0 Hz, 3H; CH3), 1.16 ppm (t, J=
7.0 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=170.6, 170.5, 148.9,
148.9, 130.6, 124.8, 124.8, 117.2, 117.1, 62.9, 61.6, 61.2, 44.1, 14.0,
13.8 ppm; [a]RDT =+162 (c=1.0 in CHCl3), (95% ee); HRMSC 15H17NO6
[M+Na]+ ; calcd: 330.0954, found: 330.0949.
7h: The ee was determined by HPLC using a Daicel Chiralcel OD
column (hexane/iPrOH (90/10); flow rate 1.0 mLminÀ1; tmajor =6.2 min;
tminor =7.3 min). 1H NMR (400 MHz, CDCl3): d=7.17 (s, 1H; ArH), 7.14
(d, J=8.6 Hz, 1H; ArH), 7.00 (d, J=8.6 Hz, 1H; ArH), 6.46 (brs, 1H;
NH), 4.30 4.11 (m, 2H; OCH2), 3.70 (s, 3H; OCH3), 2.30 (s, 3H;
ArCH3), 1.48 (s, 3H; CH3), 1.25 (t, J=7.2 Hz, 3H; CH2CH3), 1.14 ppm
(s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=176.8, 169.6, 149.6, 148.0,
133.4, 131.1, 127.6, 116.8, 113.9, 67.5, 62.5, 53.5, 52.6, 22.7, 22.1, 20.9,
13.8 ppm; [a]RDT =+96.3 (c=1.0 in CHCl3), (84% ee); HRMSC 17H21NO6
[M+Na]+ ; calcd: 358,1267, found: 358.1273.
7d: The ee was determined by HPLC using a Daicel Chiralcel OD
column (hexane/iPrOH (85/15); flow rate 1.0 mLminÀ1; tmajor =22.5 min;
tminor =27.5 min). 1H NMR (400 MHz, CDCl3):
d 7.44 7.36 (m, 4H;
ArH), 7.21 (t, J=7.5 Hz, 1H; ArH), 7.13 (t, J=7.5 Hz, 1H; ArH), 7.07
7.01 (m, 3H; ArH), 6.51 (s, 1H; NH), 4.24 4.07 (m, 2H; OCH2), 3.86 (d,
J=17.9 Hz, 1H; CHH), 3.08 (d, J=17.9 Hz, 1H; CHH), 1.16 ppm (t, J=
7.1 Hz, 3H; CH2CH3); 13C NMR (100 MHz, CDCl3): d=170.4, 169.6,
149.9, 149.0, 148.8, 130.9, 129.6, 126.5, 125.0, 124.8, 121.2, 117.4, 116.8,
63.3, 61.4, 44.5, 13.9 ppm; [a]RDT =+133 (c=1.0 in CHCl3), (92% ee);
HRMSC 19H17NO6 [M+Na]+ ; calcd: 378.0954, found: 378.0969.
7i: The ee was determined by HPLC using a Daicel Chiralcel OJ column
(hexane/iPrOH (95/5); flow rate 1.0 mLminÀ1; tmajor =21.0 min; tminor
=
25.4 min). 1H NMR (400 MHz, CDCl3): d=7.02 (d, J=9.0 Hz, 1H;
ArH), 6.95 (d, J=2.7 Hz, 1H; ArH), 6.90 (dd, J=9.0, 2.8 Hz, 1H; ArH),
6.43 (brs, 1H; NH), 4.31 4.14 (m, 2H; OCH2CH3), 3.77 (s, 3H; OCH3),
3.72 (s, 3H; OCH3), 1.51 (s, 3H; CH3), 1.27 (t, J=7.3 Hz, 3H;
OCH2CH3), 1.18 ppm (s, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=
176.7, 169.5, 155.4, 149.7, 144.1, 117.8, 115.8, 115.1, 112.7, 67.6, 62.6, 55.6,
53.6, 52.6, 22.8, 22.1, 13.8 ppm; [a]RDT =+76.0 (c=1.0 in CHCl3), (91%
ee); HRMSC 17H21NNaO7 [M+Na]+ ; calcd: 374.1216, found: 374.1220.
anti-7e: The ee was determined by HPLC using a Daicel Chiralcel OD
column (hexane/iPrOH (90/10); flow rate 1.0 mLminÀ1; tmajor =13.0 min;
tminor =26.0 min). 1H NMR (400 MHz, CDCl3): d=7.49 (d, J=7.7 Hz,
1H; ArH), 7.26 (t, J=7.3 Hz, 1H; ArH), 7.08 (t, J=7.3 Hz, 1H; ArH),
6.98 (d, J=8.1 Hz, 1H; ArH), 6.93 (s, 1H; NH), 4.21 (m, 2H; OCH2),
3.38 3.46 (m, 4H, OCH3; CH), 1.24 (t, J=7.7 Hz, 3H; CH3), 1.18 ppm
(d, J=5.1 Hz, 3H; CH3); 13C NMR (100 MHz, CDCl3): d=172.1, 169.3,
149.7, 149.0, 130.3, 126.0, 124.4, 116.8, 116.7, 65.0, 63.1, 52.0, 48.9, 13.9,
12.4 ppm; [a]DRT =+50 (c=1.0 in CHCl3), (93% ee); HRMSC 15H17NO6
[M+Na]+ ; calcd: 330.0954, found: 330.0951.
7j: The ee was determined by HPLC using a Daicel Chiralcel OJ column
(hexane/iPrOH (90/10); flow rate 1.0 mLminÀ1; tmajor =6.6 min; tminor
=
8.7 min). 1H NMR (400 MHz, CDCl3): d=7.19 (dd, J=9.5, 2.2 Hz, 1H;
ArH), 7.09 7.04 (m, 2H; ArH), 6.51 (brs, 1H; NH), 4.33 4.14 (m, 2H;
OCH2CH3), 3.71 (s, 3H; OCH3), 1.48 (s, 3H; CH3), 1.27 (t, J=7.1 Hz,
3H; OCH2CH3), 1.17 ppm (s, 3H; CH3); 13C NMR (100 MHz, CDCl3):
d=176.3, 169.2, 159.4, 157.0, 149.1, 146.3, 118.5, 118.4, 117.7, 117.4, 116.0,
115.9, 114.6, 114.3, 67.4, 62.9, 53.7, 52.7, 22.6, 22.0, 13.8 ppm; [a]RDT =+
122.2 (c=1.0 in CHCl3), (89% ee); HRMSC 16H18FNO6 [M+Na]+ ; calcd:
362,1016, found: 362.1012.
syn-7e: The ee was determined by HPLC using a Daicel Chiralcel AD
column (hexane/iPrOH (95/5); flow rate 1.0 mLminÀ1; tmajor =20.1 min;
tminor =28.2 min). 1H NMR (400 MHz, CDCl3): d=7.22 7.34 (m, 2H;
ArH), 7.09 (t, J=7.7 Hz, 1H; ArH), 7.01 (d, J=8.0 Hz, 1H; ArH), 6.50
(s, 1H; NH), 4.12 (m, 2H; OCH2), 3.69 (s, 3H; OCH3), 3.58 (q, J=
7k: The ee was determined by HPLC using a Daicel Chiralcel OD
column (hexane/iPrOH (90/10); flow rate 1.0 mLminÀ1; tmajor =8.3 min;
6152
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2003, 9, 6145 6154