Synthesis of Cyclopropane Amino Acids
CHHCCO2), 2.93 (1H, dd, J ) 9.7 and 8.4 Hz, CHPh), 4.87
and 4.96 (2H, AB system, J AB ) 13.2 Hz, COOCH2), 5.37 (1H,
br s, NH), 7.06 (2H, d, J ) 8.8 Hz, aryl H), 7.21-7.33 (3H, m,
aryl H), 7.33 (2H, br d, J ) 8.8 Hz, aryl H), 8.06 (2H, d, 8.8
Hz, aryl H); 13C NMR (68 MHz, CDCl3) δ 21.1 (t), 28.4 (3q),
35.7 (d), 41.0 (s), 65.3 (t), 80.3 (s), 123.5 (2d), 127.2 (d), 128.2
(2d), 128.2 (2d), 129.4 (2d), 135.2 (s), 142.9 (s), 147.6 (s), 155.9
(s), 170.0 (s); IR νmax/cm-1 3386, 1714, 1605, 1509, 1346, 1250,
1151, 1061, 923, 734, 696; MS m/z (EI) 413 ([MH]+, 20), 357
(32), 313 (14), 220 (14), 176 (65), 159 (24), 137 (28), 130 (30),
104 (29), 78 (26), 57 (100). Anal. Calcd for C22H24N2O6: C,
64.07; H, 5.87; N, 6.79. Found: C, 63.88; H, 5.87; N, 6.49. Data
for (Z)-9: colorless solid; eluent petroleum ether/EtOAc, 3:1;
Rf ) 0.30; mp 157-158 °C (EtOAc/petroleum ether); 1H NMR
(400 MHz, CDCl3) δ 1.32 (9H, s, C(CH3)3), 1.78 (1H, dd, J )
8.8 and 4.8 Hz, CHHCCO2), 2.16 (1H, dd, J ) 8.8 and 4.8 Hz,
CHHCCO2), 3.03 (1H, t, J ) 8.8 Hz, CHPh), 4.64 (1H, br s,
NH), 5.26 and 5.34 (2H, AB system, J AB ) 13.6 Hz, COOCH2),
7.20 (2H, d J ) 7.0 Hz, aryl H), 7.26-7.35 (3H, m, aryl H),
7.54 (2H, d, J ) 8.4 Hz, aryl H), 8.22 (2H, d, J ) 8.4 Hz, aryl
H); 13C NMR (68 MHz, CDCl3) δ 22.0 (t), 28.2 (3q), 33.3 (d),
39.8 (s), 65.8 (t), 80.2 (s), 123.8 (2d), 127.4 (d), 128.1 (2d), 128.4
(2d), 129.8 (2d), 134.2 (s), 143.2 (s), 147.8 (s), 155.7 (s), 172.2
(s); IR νmax/cm-1 3375, 2972, 1720, 1687, 1607, 1505, 1339,
1286, 1241, 1160, 844, 698. Anal. Calcd for C22H24N2O6: C,
64.07; H, 5.87; N, 6.79. Found: C, 63.72; H, 6.13; N, 6.87.
benzyltriethylammonium chloride (11 mg, 0.05 mmol), 5 (645
mg, 2 mmol), and anhydrous toluene (4 mL). The mixture was
vigorously stirred for 60 h at 40 °C. Water (10 mL) was added
to the mixture, which was then washed with DCM (3 × 25
mL). The organic layer was separated and dried over Na2SO4.
After filtration, the solvent was evaporated under reduced
pressure to give a residue. The crude material was purified
by flash chromatography (eluent petroleum ether/EtOAc, 6:1)
to afford (E)-20 (242 mg, 45%) and (Z)-20 (13 mg, 2%). Data
for (E)-20: colorless oil; EtOAc/petroleum ether, 1:6; Rf ) 0.20;
1H NMR (400 MHz, CDCl3) δ 0.15 (6H, s, Si(CH3)2), 0.96 (9H,
s, SiC(CH3)3), 1.47 (9H, s, COOC(CH3)3), 1.64 (1H, dd, J ) 6.8
and 5.4 Hz, CHHCCO2), 2.18 (1H, dd, J ) 8.3 and 5.4 Hz,
CHHCCO2), 2.85 (1H, dd, J ) 8.3 and 6.8 Hz, ArCH), 4.89
and 4.97 (2H, AB system, J AB ) 13.7 Hz, COOCH2), 5.44 (1H,
br s, NH), 6.69 (1H, d, J ) 8.3 Hz, aryl H), 6.81 (1H, s, aryl
H), 6.93 (1H, d, J ) 5.9 Hz, aryl H), 7.09 (1H, dd, J ) 8.3 and
5.9 Hz, aryl H), 7.10 (2H, d, J ) 8.8 Hz, aryl H), 8.07 (2H, d,
J ) 8.8 Hz, aryl H); 13C NMR (100 MHz, CDCl3) δ -4.4 (2q),
18.2 (s), 21.1 (t), 25.7 (3q), 28.4 (3q), 35.3 (d), 41.2 (s), 65.3 (t),
80.4 (s), 119.0 (d), 121.2 (d), 122.4 (d), 123.6 (2d), 128.2 (2d),
129.1 (d), 136.7 (s), 142.8 (s), 147.6 (s), 155.7 (s), 155.8 (s), 169.9
(s); IR νmax/cm-1 2931, 2859, 1722, 1604, 1583, 1523, 1486,
1347, 1251, 1146, 1107, 1053, 1004, 917, 831, 779, 737, 692;
MS m/z (EI) 543 ([MH]+, 10), 385 (30), 306 (35), 289 (50);
HRMS ([M - Boc]+) m/z found 441.1857, C23H29N2O5Si re-
quires 441.1846. Anal. Calcd for C28H38N2O7Si: C, 61.97; H,
7.06; N, 5.16. Found: C, 62.33; H, 7.02; N, 5.23. Data for (Z)-
20: colorless oil characterized from an enriched mixture of
both diastereoisomers; EtOAc/petroleum ether, 1:6; Rf ) 0.15;
1H NMR (400 MHz, CDCl3) δ 0.19 (6H, s, Si(CH3)2), 0.98 (9H,
s, SiC(CH3)3), 1.35 (9H, s, COOC(CH3)3), 1.72 (1H, dd, J ) 7.8
and 5.4 Hz, CHHCCO2), 2.17 (1H, dd, J ) 9.8 and 5.4 Hz,
CHHCCO2), 2.94 (1H, dd, J ) 9.8 and 7.8 Hz, ArCH), 5.22
and 5.36 (2H, AB system, J AB ) 14.2 Hz, COOCH2), 6.63 (1H,
s, aryl H), 6.76 (1H, d, J ) 7.8 Hz, aryl H), 6.82 (1H, d, J )
7.8 Hz, aryl H), 7.18 (1H, t, J ) 7.8 Hz, aryl H), 7.54 (2H, d,
J ) 8.8 Hz, aryl H), 8.22 (2H, d, J ) 8.8 Hz, aryl H); 13C NMR
(100 MHz, CDCl3) δ -4.3 (2q), 18.3 (s), 22.3 (t), 25.7 (3q), 29.8
(3q), 35.3 (d), 39.6 (s), 65.8 (t), 80.2 (s), 119.3 (d), 120.1 (d),
122.4 (d), 123.8 (2d), 128.1 (2d), 129.4 (d), 135.7 (s), 143.1 (s),
147.8 (s), 155.8 (s), 155.8 (s), 172.2 (s).
Rep r esen ta tive P r oced u r e for th e Cyclop r op a n a tion
of 7 Usin g Dia zo Com p ou n d s Gen er a ted fr om Tosylh y-
d r a zon e Sod iu m Sa lts in Situ (Ta ble 1, En tr y 11). See
Ta ble 1, Meth od c, a n d Ta ble 2, Meth od c. A mixture of
benzaldehyde tosylhydrazone sodium salt (445 mg, 1.5
mmol), benzyltriethylammonium chloride (17 mg, 0.075 mmol),
ClFeTPP (10 mg, 0.015 mmol), 7 (429 mg, 3 mmol), and
anhydrous toluene (5 mL) was vigorously stirred for 60 h at
40 °C. Water (10 mL) was added to the mixture, which was
then washed with CH2Cl2 (3 × 25 mL), and the combined
organic layers were dried over Na2SO4. After filtration, the
solvent was evaporated under reduced pressure to give the
crude material, which was purified by column chromatography
(petroleum ether/EtOAc, 10:1) to afford (E)-10 (56 mg, 16%)
and (Z)-10 (237 mg, 68%). Data for (E)-10: colorless solid;
eluent ether/MeOH, 99:1; Rf ) 0.20; mp 146-148 °C (EtOAc/
1
petroleum ether); H NMR (400 MHz, CDCl3) δ 1.59 (1H, dd,
Rep r esen ta tive P r oced u r e for th e Ca ta lytic Cyclo-
p r op a n a tion of 7 via in Situ Gen er a tion of Dia zo Com -
p ou n d s fr om Tosylh yd r a zon es (Ta ble 2, En tr y 12). See
Ta ble 2, Meth od d . To a solution of 23 (606.9 mg, 1.5 mmol)
in anhydrous THF (5 mL) at -78 °C was added, under
nitrogen, a 1 M solution of LiHMDS in THF (1.5 mL, 1.5
mmol). After being stirred at -78 °C for 15 min, the mixture
was warmed to rt, and the solvent was evaporated under
reduced pressure. To the resultant salt were added benzyltri-
ethylammonium chloride (17 mg, 0.075 mmol), ClFeTPP (11
mg, 0.015 mmol), 7 (429 mg, 3 mmol), and anhydrous toluene
(5 mL). The mixture was vigorously stirred for 3 days at 40
°C. Water (10 mL) was added to the mixture, which was then
washed with DCM (3 × 25 mL) and dried over Na2SO4. After
filtration, the solvent was evaporated under reduced pressure
to give a residue, which was purified by flash chromatography
(eluent petroleum ether/EtOAc, 1:1) to afford methyl (1R*,2S*)-
and (1R*,2R*)-1-(acetylamino)-2-(3-[1-(tert-butyl)-1,1-dimeth-
ylsilyl]oxyphenyl)-1-cyclopropanecarboxylate (21). Data for (E)-
21: colorless oil (7% yield); EtOAc/petroleum ether, 1:1; Rf )
0.15; 1H NMR (400 MHz, CDCl3) δ 0.18 (6H, s, Si(CH3)2), 0.97
(9H, s, SiC(CH3)3), 1.59 (1H, dd, J ) 9.9 and 5.5 Hz, CHH-
CCO2), 2.05 (3H, s, CH3CONH), 2.21 (1H, dd, J ) 8.4 and 5.5
Hz, CHHCCO2), 2.77 (1H, dd, J ) 9.9 and 8.4 Hz, ArCH), 3.34
(3H, s, COOCH3), 6.33 (1H, br s, NH), 6.73 (1H, dd, J ) 8.1
and 1.8 Hz, aryl H), 6.83 (1H, d, J ) 1.8 Hz, aryl H) 6.92 (1H,
d, J ) 7.7 Hz, aryl H), 7.12 (1H, dd, J ) 8.1 and 7.7 Hz, aryl
H); 13C NMR (100 MHz, CDCl3) δ -4.3 (2q), 18.3 (s) 20.5 (t),
23.3 (q), 25.8 (3q), 34.4 (d), 40.7 (s), 51.9 (q), 118.9 (d), 121.1
(d), 122.3 (d), 129.0 (d), 136.8 (s), 155.5 (s), 170.0 (s), 171.1 (s);
J ) 9.8 and 5.6 Hz, CHHCCO2), 2.04 (3H, s, CH3CONH), 2.24
(1H, dd, J ) 8.3 and 5.6 Hz, CHHCCO2), 2.84 (1H, dd, J ) 9.8
and 8.3 Hz, CHPh), 3.32 (3H, s, OCH3), 6.84 (1H, br s, NH),
7.21-7.35 (5H, m, aryl H); 13C NMR (100 MHz, CDCl3) δ
20.5 (t), 23.2 (q), 34.7 (d), 40.7 (s), 51.9 (q), 127.1 (d), 128.0
(2d), 129.3 (2d), 135.3 (s), 170.2 (s), 171.4 (s); MS m/z (EI)
234 ([MH]+, 62), 201 (82), 190 (99), 159 (79), 130 (100), 115
(48), 103 (64), 91 (48), 77 (55); HRMS m/z found 233.1052,
C
13H15NO3 requires 233.1052. Data for (Z)-10: colorless solid;
eluent ether/MeOH, 99:1; Rf ) 0.25; 1H NMR (270 MHz,
CDCl3) δ 1.73 (1H, dd, J ) 7.9 and 6.0 Hz, CHHCCO2), 1.81
(3H, s, CH3CONH), 2.18 (1H, dd, J ) 9.7 and 6.0 Hz,
CHHCCO2), 2.95 (1H, dd, J ) 9.7 and 7.9 Hz, CHPh), 3.73
(3H, s, OCH3), 5.57 (1H, br s, NH), 7.14-7.36 (5H, m, aryl H);
13C NMR (100 MHz, CDCl3) δ 21.2 (t), 23.0 (q), 32.6 (d), 39.1
(s), 52.8 (q), 127.6 (d), 128.6 (2d), 128.7 (2d), 134.3 (s), 171.3
(s), 172.1 (s); MS m/z (EI) 233 (M+, 46), 215 (47), 201 (51), 190
(83), 159 (69), 130 (100), 115 (33), 104 (58), 91 (28), 84 (49) 77
(41); HRMS m/z found 233.1055, C13H15NO3 requires 233.1052.
Rep r esen ta tive P r oced u r e for th e Ca ta lytic Cyclo-
p r op a n a tion of 5 via in Situ Gen er a tion of Dia zo Com -
p ou n d s fr om Tosylh yd r a zon es (Ta ble 2, En tr y 11, a n d
Sch em es 3 a n d 4). See Ta ble 2, Meth od b. To a solution of
3-(tert-butyldimethylsilyloxy)benzaldehyde tosylhydrazone (23)
(404.6 mg, 1 mmol) in anhydrous THF (4 mL) at -78 °C was
added under nitrogen a solution of 1 M LiHMDS in THF (1
mL, 1 mmol). After being stirred at -78 °C for 15 min, the
mixture was warmed to rt, and the solvent was evaporated
under reduced pressure. To the resultant salt were added
J . Org. Chem, Vol. 68, No. 24, 2003 9439