Synthesis of a Polymer-Supported Chiral Alcohol Auxiliary
J . Org. Chem., Vol. 66, No. 17, 2001 5863
× 10 mm), flow: 1 mL/min, H2O/CH3CN/0.1% TFA gradient 0
f 100% (15 min) and 100% (4 min); column B: Chirasphere,
5 µm (250 × 10 mm), flow: 1 mL/min, hexane/2-propanol, 97/
3; column C: Chiracel OD, 5 µm (250 × 10 mm), flow: 1 mL/
min, hexane/2-propanol: 90/10; column D: (S,S)-Whelk 01, 5
µm (250 × 10 mm), flow: 1 mL/min, hexane/2-propanol/AcOH,
eluent A: 90/10/0.5; eluent B: 99/1/0.5.
ethyl acetate (40 mL) and under argon atmosphere. The
mixture was then stirred for 3 h at room temperature under
H2 (the reaction was monitored by TLC). After filtration
through Celite, concentration of the filtrate yielded the ex-
pected compound 7 (2.1 g, 8.8 mmol, 100%): mp 120.8 °C; tR
(HPLC, column A) 9.13 min; IR (KBr) 3296 (br), 2972 (s), 2926
(m), 2876 (m), 1738 (s) 1697 (s), cm-1; MS (ESI) m/z 187.9,
244.0 [(M + H)+], 487.3, 509.2; 1H NMR (CDCl3) δ 1.05 (s, 3H,
CH3), 1.16 (s, 3H, CH3), 1.38 (s, 9H, OC(CH3)3), 3.05 (d, J )
9.3, 1H, HCH-5), 3.25 (d, J ) 9.3, 1H, HCH-5), 3.80 (d, J )
17.4, 1H, NHCHCO), 3.96 (d, J ) 17.4, 1H, NHCHCO), 3.98
(d, J ) 3.9, 1H, CH-3), 4.28 (d, J ) 3.9, 1H, OH); 13C NMR
(CDCl3) δ 20.62 (CH3), 25.25 (CH3), 28.45 (OC(CH3)3), 39.11
(C-4), 45.31 (NCH2CO), 58.07 (C-5), 77.83 (C-3), 82.69 (OC-
(R S )-3-Be n zyloxy-4,4-d im e t h yld ih yd r ofu r a n -2-on e
((RS)-4). (RS)-3-benzyloxy-4,4-dimethyldihydrofuran-2-one
((RS)-4) was obtained by the synthetic route described by
Dueno et al.12 starting from commercial (RS)-pantolactone:
93% yield; mp 48.1 °C; tR (HPLC, column A) 12.04 min; IR
(KBr) 2963 (m), 2876 (w), 1763 (m), 1783 (s), 1763 (s), 1456
1
(m), 1120 (s) cm-1; MS (ESI) m/z 221.0 [(M + H)+]; H NMR
(CDCl3) δ 1.06 (s, 3H, CH3), 1.10 (s, 3H, CH3), 3.70 (s, 1H, CH-
3), 3.82 (d, J ) 8.8 Hz, 1H, HCH-5), 3.95 (d, J ) 8.8 Hz, 1H,
HCH-5), 4.72 (d, J ) 12.1 Hz, 1H, HCH-C6H5), 5.06 (d, J )
12.1 Hz, 1H, HCH-C6H5), 7.30 (m, 5H, H-arom); 13C NMR
(CDCl3) δ 19.75 (CH3), 23.64 (CH3), 40.78 (C-4), 72.81 (CH2-
C6H5), 76.76 (C-5), 80.93 (C-3), 128.41, 128.44, 137.74 (C-arom),
175.83 (C-2). Anal. Calcd for C13H16O3 (220.26): C, 70.89; H,
7.32. Found: C, 70.84; H, 7.35.
(CH3)3), 167.76 (CO2tBu), 175.72 (C-2). Anal. Calcd for C12H21-
NO4 (243.30): C, 59.24; H, 8.70; N, 5.76; O, 26.30. Found: C,
59.09; H, 9.13; N, 5.74; O, 26.14.
3-(4,7,7-Tr im eth yl-3-oxo-2-oxa bicyclo[2.2.1]h ep ta n e-1-
ca r b on yloxy)-4,4-d im et h yl-2-oxop yr r olid in -3-yl)a cet ic
Acid ter t-Bu tyl Ester (8). To a mixture of (RS)-(3-hydroxy-
4,4-dimethyl-2-oxopyrrolidin-1-yl)acetic acid tert-butyl ester
(RS)-7 (2.0 g, 8.2 mmol) and (1S)-camphanic acid chloride (1.9
g, 9.0 mmol) in 80 mL of dry CH2Cl2 were added at 0 °C
4-(dimethylamino)pyridine (1.5 g, 12.3 mmol, 1.5 equiv) and
triethylamine (1.7 mL, 12.3 mmol, 1.5 equiv). The mixture was
then stirred at room temperature for 12 h. The resulting
mixture was filtered and washed successively with a 1 N HCl
solution (80 mL) and a saturated NaHCO3 solution (80 mL),
dried with Na2SO4, and concentrated in vacuo. Column chro-
matography on silica gel, eluting with diethyl ether/hexane
(7/3), afforded a pure mixture of (1′S,3S)/(1′S,3R) esters 8 in
91% yield (3.2 g, 7.5 mmol). The diastereoisomers (1′S,3R)-8
(0.87 g, 25% yield, 99% de) and (1′S,3S)-8 (0.62 g, 18% yield,
95% de) were isolated after flash column chromatrography on
silica gel, eluting with diethyl ether/hexane. The diastereo-
isomer (1′S,3S)-8 was also isolated after recrystallization from
2-propanol (21% yield, 99% de). Crystallization of an aliquot
of compound (1′S,3R)-8 from AcOEt/hexane yielded colorless
crystals suitable for X-ray analysis.
(RS)-3-Ben zyloxy-4,4-d im eth ylp yr r olid in -2-on e ((RS)-
5). A solution of compound (RS)-4 (3.5 g, 15.9 mmol) in 30 mL
of aqueous ammonia was heated at 230 °C for 9 h in a sealed
tube. The mixture was then allowed to warm to room temper-
ature, and the volatile products were eliminated at reduced
pressure. The expected compound (RS)-5, which precipitated
upon addition of ether, was collected by filtration and dried
in vacuo over phosphorus pentoxide: 80% yield (2.8 g, 12.7
mmol); mp 132.5 °C; tR (HPLC, column A) 10.24 min; IR (KBr)
3300-2600 (br), 1966 (m), 1712 (s), 1456 (m) cm-1; MS (ESI)
m/z 220.1 [(M + H)+], 242.0, 439.1; 1H NMR (CDCl3) δ 1.10 (s,
3H, CH3), 1.15 (s, 3H, CH3), 3.03 (d, J ) 9.6, 1H, HCH-5), 3.09
(d, J ) 9.6, 1H, HCH-5), 3.62 (s, 1H, CH-3), 4.75 (d, J ) 12.2,
1H, HCH-C6H5), 5.10 (d, J ) 12.2, 1H, HCHC6H5), 7.40 (m,
5H, H-arom); 13C NMR (CDCl3) δ 21.08 (CH3), 25.80 (CH3),
40.55 (C-4), 52.85 (C-5), 73.14 (CH2C6H5), 83.47 (C-3), 128.07,
128.20, 128.34, 128.54, 128.74, 138.61 (C-arom), 177.31 (C-2).
Anal. Calcd for C13H17NO2 (219.28): C, 71.21; H, 7.81; N, 6.39.
Found: C, 71.45; H, 7.95; N, 6.51.
(RS)-(3-Ben zyloxy-4,4-d im eth yl-2-oxop yr r olid in -1-yl)-
a cetic Acid ter t-Bu tyl Ester ((RS)-6). To a solution of
compound (RS)-5 (2.0 g, 9.1 mmol) in 60 mL of freshly distilled
THF was slowly added at -10 °C sodium hydride (0.7 g, 18.2
mmol, 60% in paraffin). After the mixture was stirred for 15
min at room temperature, tert-butyl bromoacetate (1.5 mL,
10.0 mmol) was added dropwise and stirring was continued
for 12 h at the same temperature (TLC indicated complete
consumption of the starting material). The reaction mixture
was neutralized with 1 N HCl. The THF was concentrated in
vacuo and the aqueous layer extracted with ethyl acetate
(twice). The combined organic layer was dried over anhydrous
sodium sulfate and concentrated in vacuo. Column chroma-
tography on silica gel, eluting with hexane/ethyl acetate (6/
2), yielded the pure compound (RS)-6 as a colorless oil (2.9 g,
8.8 mmol, 96%): tR (HPLC, column A) 14.15 min; IR (CH2Cl2)
2968 (m), 2931 (m), 2872 (w), 1740 (s), 1701 (s), 1453 (m), 1369
(m), 1154 (s) cm-1; MS (ESI) m/z: 278.0, 334.1 [(M + H)+],
667.6, 689.7; 1H NMR (CDCl3) δ 1.10 (s, 3H, CH3), 1.15 (s, 3H,
CH3), 1.45 (s, 9H, OC(CH3)3), 3.05 (d, J ) 9.1, 1H, HCH-5),
3.15 (d, J ) 9.1, 1H, HCH-5), 3.62 (s, 1H, CH-3), 3.75 (d, J )
17.3, 1H, NHCHCO), 4.08 (d, J ) 17.3, 1H, NHCHCO), 4.73
(d, J ) 12.1, 1H, HCHC6H5), 5.05 (d, J ) 12.1, 1H, HCHC6H5),
7.35 (m, 5H, H-arom); 13C NMR (CDCl3) δ 21.23 (CH3), 25.70
(CH3), 28.49 (OC(CH3)3), 38.37 (C-4), 45.08 (NCH2CO), 58.08
(C-5), 72.95 (CH2C6H5), 82.55 (OC(CH3)3), 83.44 (C-3), 128.00,
128.21, 128.68, 138.66 (C-arom), 167.98 (CO2tBu), 173.76 (C-
2); HRMS (FAB) calcd for C19H28NO4 (MH+) 334.2018, found
334.1992.
Compound (1′S,3S)-8: mp 153.0 °C; [R]20 ) -26 (c ) 1.1
D
in CH2Cl2); tR (HPLC, column A) 12.88 min; (HPLC, column
B) 19.5 min; IR (KBr) 2973 (s), 2928 (m), 2883 (m), 1797 (s),
1742 (s), 1712 (s) cm-1; MS (ESI) m/z 367.1, 424.1 [(M + H)+],
847.7; 1H NMR (CDCl3) δ 0.90 (s, 3H, CH3), 0.92 (s, 3H, CH3),
0.96 (s, 3H, CH3), 1.01 (s, 3H, CH3), 1.10 (s, 3H, CH3), 1.30 (s,
9H, OC(CH3)3), 1.52 (ddd, J ) 13.2, 9.3, 4.2, 1H, HCH-5′), 1.78
(ddd, J ) 13.2, 10.8, 4.5, 1H, HCH-5′), 1.91 (ddd, J ) 13.7,
9.3, 4.5, 1H, HCH-6′), 2.37 (ddd, J ) 13.7, 10.8, 4.2, 1H, HCH-
6′), 2.99 (d, J ) 9.2, 1H, HCH-5), 3.18 (d, J ) 9.2, 1H, HCH-
5), 3.73 (d, J ) 17.5, 1H, NHCHCO), 3.84 (d, J ) 17.5, 1H,
NHCHCO), 5.26 (s, 1H, CH-3); 13C NMR (CDCl3) δ 10.18 (CH3),
17.02 (CH3), 17.16 (CH3), 21.78 (CH3), 25.27 (CH3), 28.46 (OC-
(CH3)3), 29.19 (C-5′), 31.03 (C-6′), 38.12 (OC(CH3)3), 45.23 (N-
CH2-CO), 54.90 (C-7′), 55.38 (C-4′), 57.97 (C-5), 78.92 (C-3),
82.87 (C-4), 91.65 (C-1′), 167.34, 167.51, 169.71, 178.77 (CO).
Anal. Calcd for C22H33NO7 (423.50): C, 62.39; H, 7.85; N, 3.31;
O, 26.45. Found: C, 62.22; H, 8.23; N, 3.35; O, 26.37.
Compound (1′S,3R)-8: mp 133.6 °C; [R]20 ) +26 (c ) 1.1
D
in CH2Cl2); tR (HPLC, column A) 12.88 min; (HPLC, column
B) 14.5 min; IR (KBr) 2973 (s), 2928 (m), 2883 (m), 1797 (s),
1742 (s), 1712 (s) cm-1; MS (ESI) m/z 367.1, 424.1 [(M + H)+],
847.7; 1H NMR (CDCl3) δ 0.88 (s, 3H, CH3), 0.94 (s, 3H, CH3),
0.98 (s, 3H, CH3), 1.00 (s, 3H, CH3), 1.10 (s, 3H, CH3), 1.30 (s,
9H, OC(CH3)3), 1.55 (ddd, J ) 13.4, 9.4, 4.3, 1H, HCH-5′), 1.73
(ddd, J ) 13.9, 10.9, 4.5, 1H, HCH-5′), 1.87 (ddd, J ) 13.9,
9.4, 4.5, 1H, HCH-6′), 2.30 (ddd, J ) 13.4, 10.9, 4.3, 1H, HCH-
6′), 2.99 (d, J ) 9.2, 1H, HCH-5), 3.18 (d, J ) 9.2, 1H, HCH-
5), 3.73 (d, J ) 17.5, 1H, NHCHCO), 3.82 (d, J ) 17.5, 1H,
NHCHCO), 5.22 (s, 1H, CH-3); 13C NMR (CDCl3) δ 10.12 (CH3),
16.81 (CH3), 17.03 (CH3), 17.05 (CH3), 21.77 (CH3), 28.46 (OC-
(CH3)3), 29.51 (C-5′), 31.01 (C-6′), 38.13 (OC(CH3)3), 45.22
(NCH2CO), 55.02 (C-7′), 55.22 (C-4′), 57.92 (C-5), 78.62 (C-3),
82.92 (C-4), 91.48 (C-1′), 166.93, 167.51, 169.74, 178.40 (CO).
Anal. Calcd for C22H33NO7 (423.50): C, 62.39; H, 7.85; N, 3.31;
O, 26.45. Found: C, 62.77; H, 8.11; N, 3.35; O, 26.47.
(RS)-(3-H yd r oxy-4,4-d im et h yl-2-oxop yr r olid in -1-yl)-
a cetic Acid ter t-Bu tyl Ester ((RS)-7). (RS)-(3-Benzyloxy-
4,4-dimethyl-2-oxopyrrolidin-1-yl)acetic acid tert-butyl ester 6
(2.9 g, 8.8 mmol) in ethyl acetate (40 mL) was added to a cooled
solution (-20 °C) of 10% palladium hydroxide on charcoal in