(m, 2H), 4.78 (d, J ) 6.9 Hz, 1H), 5.08-5.13 (m, 2H), 5.72-5.76
(m, 2H), 7.28-7.66 (m, 15H) ppm. ESI-MS (m/z, %): 697.2 (M
+ Na+, 100%). Anal. Calcd for C38H50N2O7Si (%): C, 67.63; H,
7.47; N, 4.15. Found: C, 67.82; H, 7.40; N, 3.83.
85%). [R]25D -49.2 (c 0.95, CHCl3). IR (neat): 3330, 3070, 2980,
1
2825, 1717, 1690, 1540, 1284, 1239, 1046 cm-1. H NMR (300
MHz, CDCl3): δ 1.29 (t, J ) 7.2 Hz, 3H), 1.39 (s, 9H), 2.25-
2.30 (m, 1H), 2.41 (dd, J ) 17.4, 4.5 Hz, 1H), 3.41 (s, 3H), 3.73-
3.81 (m, 2H), 4.15-4.24 (m, 3H), 4.69 (d, J ) 7.2 Hz, 1H), 4.76
(d, J ) 7.2 Hz, 1H), 4.85 (d, J ) 6.9 Hz, 1H), 5.09 (br s, 2H), 5.67
(d, J ) 7.5 Hz, 1H), 6.77 (s, 1H), 7.32 (br s, 5H) ppm. ESI-MS
(m/z, %): 379.2 (M - Boc + H+, 95%), 501.2 (M + Na+, 100%).
Anal. Calcd for C24H34N2O8 (%): C, 60.24; H, 7.16; N, 5.85.
Found: C, 60.23; H, 7.22; N, 5.60.
((1S,5R,6R)-6-tert-Butoxycarbonylamino-3-hydroxymethyl-5-
methoxymethoxy-cyclohex-3-enyl)-carbamic Acid Benzyl Ester
(19). To a stirred solution of 18 (2.0 g, 2.97 mmol) in THF (30
mL) was added TBAF (1.0 M in THF, 3.0 mL, 3.0 mmol, 1.01
equiv) at 0 °C. The reaction was stirred at room temperature for 2
h, and then saturated aqueous NH4Cl (20 mL) was added to quench
the reaction. The layers were separated, and the aqueous layer was
extracted with EtOAc (20 mL × 3). The combined organic layers
were washed with brine (20 mL × 3), dried (Na2SO4), and
concentrated. The residue was purified by flash column chroma-
tography on silica gel (petroleum ether/ethyl acetate ) 1:2) to give
(3R,4R,5S)-4-Acetylamino-5-benzyloxycarbonylamino-3-hy-
droxy-cyclohex-1-enecarboxylic Acid Ethyl Ester (22). The ester
21 (405 mg, 0.84 mmol) was treated with 5% HCl solution in EtOH
(50 mL) at 0 °C and then stirred at room temperature overnight.
EtOH was removed in vacuo, and the residue was again diluted
with EtOH (10 mL). After treatment with saturated aqueous Na2-
CO3 (10 mL), AcCl (1 mL) was added dropwise at 0 °C under
vigorous stirring. The reaction mixture was stirred for 30 min at
room temperature. EtOH was removed in vacuo, and the residue
was diluted with EtOAc (50 mL) and H2O (20 mL). The layers
were separated, and the aqueous layer was extracted with EtOAc
(20 mL × 3). The combined organic layers were washed with brine
(30 mL × 3), dried (Na2SO4), and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate ) 1:10) to afford 22 (262 mg, 83%
alcohol 19 (1.25 g, 96%) as a white wax. [R]25 -62.3 (c 0.95,
D
CHCl3). IR (neat): 3321, 3070, 2959, 2857, 1690, 1542, 1282, 1047
1
cm-1. H NMR (300 MHz, CDCl3): δ 1.37 (s, 9H), 1.79 (br s,
1H, ex. D2O), 2.10-2.19 (m, 1H), 2.41 (dd, J ) 17.1, 4.8 Hz,
1H), 3.38 (s, 3H), 3.70-3.80 (m, 2H), 4.01 (br s, 2H), 4.06-4.08
(m, 1H), 4.67 (d, J ) 7.2 Hz, 1H), 4.72 (d, J ) 6.9 Hz, 1H), 4.93
(d, J ) 8.4 Hz, 1H), 5.07 (br s, 2H), 5.66 (s, 1H), 6.02 (d, J ) 8.1
Hz, 1H), 7.32 (br s, 5H) ppm. ESI-MS (m/z, %): 459.2 (M + Na+,
100%). Anal. Calcd for C22H32N2O7 (%): C, 60.54; H, 7.39; N,
6.42. Found: C, 60.55; H, 7.47; N, 6.18.
for 2 steps). [R]22 5.56 (c 0.97, CHCl3). IR (neat): 3287, 3082,
D
(3R,4R,5S)-5-Benzyloxycarbonylamino-4-tert-butoxycarbony-
lamino-3-methoxymethoxy-cyclohex-1-enecarboxylic Acid Ethyl
Ester (21). To a stirred suspension of alcohol 19 (377 mg, 0.86
mmol) and activated 4 Å molecular sieves (220 mg) in anhydrous
CH2Cl2 (17 mL) was added PCC (186 mg, 1.03 mmol, 1.2 equiv).
The whole mixture was stirred at room temperature for 2 h, diluted
with Et2O (50 mL), and filtered through a pad of Celite. The solution
was washed successively with saturated aqueous NH4Cl (30 mL
× 3) and brine (30 mL × 3), dried (Na2SO4), and concentrated in
vacuo. The residue was purified by flash column chromatography
on silica gel (petroleum ether/ethyl acetate ) 1:1) to afford the
aldehyde as a white wax, which was used directly for the next steps
without characterization.
To a stirred solution containing freshly prepared aldehyde (0.86
mmol) and 2,3-dimethylbuta-1,3-diene (0.92 mL, 8.64 mmol, 10.0
equiv) in tert-butyl alcohol/THF/H2O (v/v/v 4:1:1, 25 mL) was
added slowly sodium chlorite (294 mg, 2.59 mmol, 3.0 equiv) and
sodium dihydrogen phosphate (353 mg, 2.59 mmol, 3.0 equiv) in
water (4 mL) under 10 °C. The resultant suspension was stirred at
room temperature for 6 h. Saturated aq NaHSO3 (10 mL) was added
to quench the reaction. The layers were separated, and the aqueous
layer was extracted with EtOAc (20 mL × 3). The combined
organic layers were washed with brine (20 mL × 3), dried (Na2-
SO4), and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (petroleum ether/ethyl acetate
) 1:10) to afford the acid 20 (342 mg, 88% for 2 steps). 1H NMR
(300 MHz, CDCl3): δ 1.38 (s, 9H), 2.23-2.31 (m, 1H), 2.80-
2.87 (m, 1H), 3.40 (s, 3H), 3.72-3.78 (m, 1H), 3.81-3.86 (m,
1H), 4.20-4.23 (m, 1H), 4.68 (d, J ) 6.9 Hz, 1H), 4.75 (d, J )
7.2 Hz, 1H), 5.08-5.12 (m, 3H), 6.04 (d, J ) 8.7 Hz, 1H), 6.84 (s,
1H), 7.31 (br s, 5H) ppm. ESI-MS (m/z, %): 473.2 (M + Na+,
100%).
2926, 2854, 1720, 1689, 1657, 1630, 1550, 1374, 1289, 1251, 1046
1
cm-1. H NMR (300 MHz, CDCl3): δ 1.29 (t, J ) 7.5 Hz, 3H),
1.86 (s, 3H), 2.16-2.26 (m, 1H), 2.86 (dd, J ) 17.1, 4.2 Hz, 1H),
3.74-3.80 (m, 1H), 3.84-3.90 (m, 1H), 4.20 (q, J ) 7.5 Hz, 2H),
4.30 (br s, 1H), 4.84 (s, 1H), 5.06 (d, J ) 12.6 Hz, 1H), 5.10 (d,
J ) 7.5 Hz, 1H), 5.19 (d, J ) 11.7 Hz, 1H), 6.78 (s, 1H), 6.95 (d,
J ) 5.7 Hz, 1H), 7.36 (br s, 5H) ppm. ESI-MS (m/z, %): 377.1
(M + H+, 100%). Anal. Calcd for C19H24N2O5 (%): C, 60.63; H,
6.43; N, 7.44. Found: C, 60.69; H, 6.64; N, 7.19.
(3R,4R,5S)-4-Acetylamino-5-amino-3-hydroxy-cyclohex-1-en-
ecarboxylic Acid Ethyl Ester (5). To a stirred suspention of Pd-
(OAc)2 (4 mg, 0.02 mmol, 0.1 equiv) in anhydrous CH2Cl2 (4 mL)
was added Et3N (7 µL, 0.05 mmol, 0.3 equiv) and Et3SiH (55 µL,
0.34 mmol, 2.0 equiv) dropwise at 0 °C under N2. After stirring at
room temperature for 15 min, a solution of 22 (64 mg, 0.17 mmol)
in anhydrous CH2Cl2 (2 mL) was added dropwise at room
temperature under N2. The reaction mixture was stirred at room
temperature for 2 h. The mixture was concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(chloroform/methanol ) 8:1) to afford 5 (38 mg, 92%) as a pale-
brown wax. [R]24D -13.8 (c 1.01, CH3OH). IR (neat): 3252, 3074,
1
2930, 1713, 1658, 1556, 1445, 1374, 1245, 1125 cm-1. H NMR
(300 MHz, CD3OD): δ 1.31 (t, J ) 7.2 Hz, 3H), 2.05 (s, 3H),
2.15-2.27 (m, 1H), 2.82 (dd, J ) 17.7, 4.5 Hz, 1H), 2.92-2.97
(m, 1H), 3.72 (dd, J ) 10.5, 9.3 Hz, 1H), 4.16-4.26 (m, 3H), 6.77
(s, 1H) ppm. 13C NMR (300 MHz, CD3OD): δ 15.0, 23.6, 33.9,
51.4, 59.9, 62.5, 71.6, 130.5, 141.3, 168.1, 175.4 ppm. ESI-MS
(m/z, %): 243.2 (M + H+, 100%). HR-MALDI-MS calcd for
C11H19N2O4 (M + H+), 243.1346; found, 243.1339.
Acknowledgment. This work was financially supported by
NSFC (20425205 and 20321202), Chinese Academy of Sciences
(KGCX2-SW-209), and Shanghai Municipal Commission of
Science and Technology (04DZ14901).
To a stirred solution of acid 20 (1.0 g, 2.2 mmol) in anhydrous
CH2Cl2 (66 mL) was added DIPEA (0.45 mL, 2.7 mmol, 1.2 equiv),
HOBt‚H2O (413 mg, 2.7 mmol, 1.2 equiv), and EDCI (518 mg,
2.7 mmol, 1.2 equiv) at 0 °C under N2. After stirring for 30 min at
0 °C, anhydrous EtOH (160 µL, 2.7 mmol, 1.2 equiv) was added
dropwise. The reaction mixture was stirred at room temperature
for 6 h. The reaction mixture was diluted with CH2Cl2 (150 mL)
and washed with saturated aqueous NH4Cl (50 mL × 3) and brine
(50 mL × 3), dried (Na2SO4), and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate ) 8:1) to afford ester 21 (899 mg,
Supporting Information Available: General experimental
methods, experimental details, and characterizations for compounds
1
7-15, H NMR spectra of compounds 5, 7-15, 17-19, 21, and
1
22, 13C NMR spectrum of compound 5, and H-1H COSY and
NOESY spectra of compounds 14 and 15 (PDF). This material is
JO060633H
5368 J. Org. Chem., Vol. 71, No. 14, 2006