K. Nakada et al. / Bioorg. Med. Chem. xxx (2013) xxx–xxx
9
evaporated. The residue was purified by column chromatography
(silica gel; hexane/AcOEt, 49:1) to give an oil (5.0 g). To a solution
of the oil in THF (56 mL) was added a mixture of aqueous HCl
(12 M, 17 mL) and THF (80 mL) at 0 C, and the resulting mixture
was stirred at the same temperature for 35 smin. To the mixture
was added aqueous saturated NaHCO3 (100 mL), and the resulting
solution was extracted with AcOEt. The organic layer was washed
with brine, dried (Na2SO4), and evaporated to give an oil (4.4 g). A
mixture of the oil and NaBH4 (206 mg, 5.5 mmol) in THF/MeOH
(4:1, 136 mL) was stirred at room temperature for 5 h, and then
aqueous HCl (1 M) was aded. The resulting mixture was extracted
with CHCl3 and the organic layer was washed with saturated aque-
ous NaHCO3 and brine, dried (Na2SO4), and evaporated. The residue
was purified by column chromatography (silica gel; hexane/AcOEt,
8:1–3:1) to give 22 (3.8 g, 66%) as an oil: 1H NMR (500 MHz, CDCl3)
d 0.27–0.33 (2H, m, H-3), 0.53–0.59 (1H, m, H-1), 0.93–1.01 (1H, m,
H-2), 1.06 (9H, s, –C(CH3)3), 1.18–1.25 (1H, m, H-10), 1.77–1.82 (1H,
m, H-10), 2.53 (1H, br s, –OH), 3.08 (1H, dd, –CHaHbOTBDPS, J = 9.2,
10.3 Hz), 3.72–3.80 (2H, m, H-20), 3.89 (1H, dd, –CHaHbOTBDPS,
J = 5.2, 10.3 Hz), 7.36–7.69 (10H, m, aromatic); 13C NMR
(125 MHz, CDCl3) d 8.3, 14.4, 19.1, 20.6, 26.8, 35.9, 63.3, 68.3,
(1H, m, H-3), 1.23–1.28 (1H, m, H-1), 1.40–1.44 (1H, m, H-3),
1.52–1.58 (1H, m, H-2), 1.59–1.66 (2H, m, H-10), 3.54 (2H, t, H-20,
J = 6.8 Hz), 4.51 (2H, s, –CH2Ph), 7.25–7.36 (5H, m, aromatic); 13C
NMR (100 MHz, CDCl3) d 16.0, 19.8, 21.0, 33.2, 69.4, 73.0, 127.6,
127.6, 128.4, 138.3, 180.7; LRMS (EI) m/z 220 (M)+; ½a D23
ꢁ45.9°
ꢂ
(c 1.03, CHCl3); Anal. Calcd for C13H16O3ꢀ0.05CHCl3: C, 69.28; H,
7.15. Found: C, 69.10; H, 7.17.
3.14. (1S,2R)-1-(2-Benzyloxy)ethyl-2-(t-
buthoxycarbonyl)aminocyclopropane (25)
A mixture of 24 (1.35 g, 6.1 mmol), (PhO)2PON3 (3.95 mL,
18 mmol), and Et3N (1.28 mL, 9.2 mmol) in CH2Cl2 (61 mL) was
stirred at room temperature for 3.5 h. The reaction mixture was
partitioned between AcOEt and H2O, and the organic layer was
washed with brine, dried (Na2SO4), and evaporated. A solution of
the residual oil in t-BuOH (61 mL) was heated under reflux for
19 h, and then evaporated. The residue was purified by column
chromatography (silica gel; AcOEt/hexane, 7:1) to give 25 (1.33 g,
75%) as an oil: 1H NMR (400 MHz, CDCl3) d 0.53–0.56 (1H, m, H-
3), 0.63–0.67 (1H, m, H-3), 0.91–0.97 (1H, m, H-1), 1.44–1.50
(10H, m, H-10 and –C(CH3)3), 1.64–1.69 (1H, m, H-10), 2.25–2.30
(1H, m, H-2), 3.57 (2H, dd, H-20, J = 6.3, 6.8 Hz), 4.52 (2H, s, –CH2-
Ph), 4.57–4.72 (1H, br, –NH), 7.26–7.34 (5H, m, aromatic); 13C
NMR (100 MHz, CDCl3) d 13.5, 17.7, 28.4, 29.1, 32.5, 69.6, 72.9,
127.6, 129.6, 133.4, 135.6; LRMS (FAB) m/z 377.2 (M+Na)+; ½a D22
ꢂ
ꢁ0.2° (c 1.28, CHCl3); Anal. Calcd for C22H30O2Si: C, 74.53; H,
8.53. Found: C, 74.39; H, 8.73.
3.12. (1S,2R)-1-(2-Benzyloxy)ethyl-2-
hydroxymethylcyclopropane (23)
79.3, 127.5, 127.6, 128.3, 138.6, 156.4; LRMS (FAB) m/z 314
(M+Na)+;
½
a 2D2
ꢂ
–25.0° (c 0.70, CHCl3); Anal. Calcd for
22
D
C
17H25NO3: C, 70.07; H, 8.65; N, 4.81. Found: C, 69.77; H, 8.45;
A mixture of 22 (3.0 g, 8.5 mmol), BnBr (2.01 mL, 17 mmol),
Bu4NI (625 mg, 1.7 mmol), and NaH (60%, 1.69 g, 42 mmol) in
DMF/THF (1/1, 170 mL) was stirred at ꢁ10 °C for 25 h. After addi-
tion of aqueous saturated NH4Cl, the solvent was evaporated, and
the residue was partitioned between AcOEt and H2O. The organic
layer was washed with brine, dried (Na2SO4) and evaporated. The
residue was purified by column chromatography (silica gel; hex-
ane/AcOEt, 30:1) to give an oil (3.17 g). A mixture of the oil and
TBAF (1.0 M in THF, 10.7 mL, 10.7 mmol) was stirred at room tem-
perature for 3 h and then evaporated. The residue was purified by
column chromatography (silica gel; hexane/AcOEt, 4:1–1.1) to give
23 (1.46 g, 7.09 mmol, 84%) as an oil: 1H NMR (500 MHz, CDCl3) d
0.34–0.43 (2H, m, H-3), 0.67–0.73 (1H, m, H-1), 0.86–0.92 (1H, m,
H-2), 1.42–1.49 (1H, m, H-10), 1.62–1.69 (1H, m, H-10), 1.71–1.77
(1H, br s, –OH), 3.28–3.31 (1H, m, –CHaHbOH), 3.52–3.57 (3H, m,
H-20 and –CHaHbOH), 4.51 (2H, s, –CH2Ph), 7.25–7.38 (5H, m, aro-
matic); 13C NMR (125 MHz, CDCl3) d 9.6, 14.3, 21.0, 33.4, 67.0, 70.2,
N, 4.65.
3.15. (1S,2R)-2-(t-Buthoxycarbonyl)amino-1-
(carboxymethyl)cyclopropane (26)
A mixture of 25 (1.33 mg, 4.6 mmol) and Pd-C (10%, 664 mg) in
THF/MeOH (1:4, 46 mL) was stired under H2 (1 atm) at room tem-
perature for 3 h. The resulting mixture was filtered with Celite and
evaporated, and the residue was purified by column chromatogra-
phy (silica gel; hexane/AcOEt, 2:1) to give an oil (949 mg). A mix-
ture of the oil and Dess–Martin periodinane (584 mg, 1.4 mmol) in
CH2Cl2 (10 mL) was stirred at 0 °C for 1 h and then at room temper-
ature for 1 h. After addition of a mixture of saturated aqueous
Na2S2O and saturated aqueous NaHCO3 (1:1), the resulting mixture
was extracted with CHCl3, and the organic layer was washed with
brine, dried (Na2SO4), and evaporated to give an oil (228 mg). A
mixture of the oil, 2-methyl-2-butene (831 mL, 7.8 mmol), NaClO2
(353 mg, 3.9 mmol), and NaH2PO4ꢀ2H2O (307 mg, 2.0 mmol) in
t-BuOH/H2O (4:1, 10 mL) was stirred at room temperature for
1 h. The resulting mixture was partitioned between AcOEt and
aqueous HCl (1 M), and the organic layer was washed with brine,
dried (Na2SO4), and evaporated. The residue was purified by col-
umn chromatography (silica gel; hexane/AcOEt, 1:1) to give 26
(192 mg, 91%) as an oil: 1H NMR (400 MHz, CDCl3) d 0.64–0.69
(1H, m, H-3), 0.85–0.91 (1H, m, H-3), 1.14–1.19 (1H, m, H-1),
1.45 (9H, s, –C(CH3)3), 1.96–2.05 (1H, m, H-10), 2.33–2.35 (1H, m,
H-2), 2.80–2.85 (1H, m, H-10), 5.08 (1H, brs, –NH); 13C NMR
(100 MHz, CDCl3) d 13.3, 15.8, 28.2, 29.2, 37.7, 80.9, 157.8, 174.5;
72.9, 127.6, 127.7, 128.3, 138.3; LRMS (EI) m/z 205 (M–H)+; ½a D22
ꢂ
+1.6° (c 0.93, CHCl3); Anal. Calcd for C13H18O2ꢀ0.15H2O: C, 74.71;
H, 8.83. Found: C, 74.84; H, 8.97.
3.13. (1S,2R)-trans-1-(2-Benzyloxy)ethyl-2-
carboxycyclopropane (24)
A mixture of 23 (528 mg, 2.6 mmol) and Dess–Martin period-
inane (1.67 g, 3.9 mmol) in CH2Cl2 (26 mL) was stirred at 0 °C for
45 min. After addition of a mixture of saturated aqueous Na2S2O
and saturated aqueous NaHCO3 (1:1), the resulting mixture was
extracted with CHCl3, and the organic layer was washed with
brine, dried (Na2SO4), and evaporated to give an oil (583 mg). A
mixture of the oil, 2-methyl-2-butene (2.17 mL, 21 mmol), NaClO2
(926 mg, 10 mmol), and NaH2PO4ꢀ2H2O (805 mg, 5.2 mmol) in
t-BuOH/H2O (24:1, 25 mL) was stirred at room temperature for
2 h. The resulting mixture was partitioned between AcOEt and
aqueous HCl (1 M), and the organic layer was washed with brine,
dried (Na2SO4), and evaporated. The residue was purified by col-
umn chromatography (silica gel; hexane/AcOEt, 4:1) to give 24
(547 mg, 97%) as an oil: 1H NMR (400 MHz, CDCl3) d 0.81–0.85
LRMS (FAB) m/z 216 (M+H)+; ½a D20
ꢂ
+44.5° (c 0.90, CHCl3); Anal.
Calcd for C10H17NO4ꢀ0.1H2O: C, 55.34; H, 7.99; N, 6.45. Found: C,
55.09; H, 7.88; N, 6.20.
3.16. (1S,2R)-2-amino-1-(carboxymethyl)cyclopropane
hydrochloride (IIa, HCl salt)
A mixture of 26 (431 mg, 2.0 mmol) and aqueous HCl (4 M,
40 mL) was stireed at room temperature for 35 min, and then eva-
ported. The residue was triturated with Et2O to give IIa (HCl salt,