Durham and Miller
22.87, 14.29; IR (neat) 2111, 1817, 1731 cm-1; FAB-HRMS m/z
calcd for C19H35N4O3 (M - H+) 367.2709 found 337.2699.
(()-tr a n s-3-Azid o-1-(ter t-bu toxyca r bon yl)-4-cyclop r o-
p yl-2-a zetid in on e (8b). Filtration through a plug of silica
(10:1 hexanes/EtOAc) provided the title compound as a clear
oil (71%): 1H NMR (CDCl3) δ 4.37 (d, J ) 2.70 Hz, 1H), 3.26
(dd, J 1 ) 8.70 Hz, J 2 ) 2.40 Hz, 1H), 1.54 (s, 9H), 1.07 (m,
1H), 0.81 (m, 1H), 0.62 (m, 2H), 0.38 (m, 1H); 13C NMR (CDCl3)
δ 162.19, 147.82, 84.09, 68.18, 64.81, 28.12, 12.24, 5.83, 1.74;
IR (neat) 2111, 1816, 1728 cm-1; FAB-HRMS m/z calcd for
53.56, 52.70, 41.22, 32.11, 30.20, 29.82, 29.74, 29.68, 29.53,
29.46, 28.53, 26.27, 22.88, 14.31; IR (KBr) 3331, 2107, 1752,
1690, 1658 cm-1; FAB-HRMS m/z calcd for C22H42N5O5 (M -
H+) 456.3186 found 456.3200.
(()-(R,R)-Met h ylglycin e-2-a zid o-3-N-(ter t-b u t oxyca r -
bon yl)-3-cyclop r op ylp r op a m id e (9b). Filtration through a
plug of silica (2:1 hexanes/EtOAc) provided the title compound
1
as a white solid (96%): mp 108-109 °C; H NMR (CDCl3) δ
6.99 (br s, 1H), 5.07 (m, 1H), 4.55 (br s, 1H), 4.08 (m, 2H),
3.78 (s, 3H), 3.39 (m, 1H), 1.46 (s, 9H), 1.01 (m, 1H), 0.51 (m,
2H), 0.34 (m, 2H); 13C NMR (CDCl3) δ 170.08, 167.73, 155.31,
80.15, 66.14, 58.50, 52.65, 41.19, 11.59, 4.68, 2.88; IR (film)
3332, 2112, 1754, 1694, 1673 cm-1; FAB-HRMS m/z calcd for
C
11H17N4O3 (M - H+) 253.1301, found 253.1320.
(()-tr a n s-3-Azido-1-(ter t-bu toxycar bon yl)-4-cycloh exyl-
2-a zetid in on e (8c). Filtration through a plug of silica (10:1
hexanes/EtOAc) provided the title compound as a clear oil
(74%): 1H NMR (CDCl3) δ 4.39 (d, J ) 3.00 Hz, 1H), 3.74 (dd,
J 1 ) 5.40 Hz, J 2 ) 3.00 Hz, 1H), 2.01 (m, 1H), 1.73 (m, 5H),
1.53 (s, 9H), 1.26 (m, 3H), 1.01 (m, 2H); 13C NMR (CDCl3) δ
162.08, 148.25, 84.20, 65.02, 64.43, 37.64, 29.25, 28.18, 26.51,
26.31, 25.94, 25.70; IR (neat) 2110, 1815, 1728 cm-1; FAB-
HRMS m/z calcd for C14H23N4O3 (M - H+) 295.1770, found
295.1783.
C
14H25N5O5 (M - H+) 342.1777 found 342.1769.
(()-(R,R)-Met h ylglycin e-2-a zid o-3-N-(ter t-b u t oxyca r -
bon yl)-3-(cycloh exyl)p r op a m id e (9c). Filtration through a
plug of silica (2:1 hexanes/EtOAc) provided the title compound
as a glass (93%): 1H NMR (CDCl3) δ 6.90 (br s, 1H), 5.10 (d,
J ) 9.90 Hz, 1H), 4.28 (m, 1H), 4.14 (dd, J 1 ) 18.30 Hz, J 2
)
5.70 Hz, 1H), 3.99 (dd, J 1 ) 18.30 Hz, J 2 ) 5.40 Hz, 1H), 3.87
(m, 1H), 3.78 (s, 3H), 1.70 (m, 5H), 1.49 (m, 10H), 1.16 (m,
5H); 13C NMR (CDCl3) δ 170.05, 168.38, 156.10, 79.82, 64.35,
57.79, 52.72, 41.25, 30.70, 28.97, 28.53, 28.14, 26.31, 26.05;
IR (KBr) 3325, 2106, 1757, 1694, 1661 cm-1; FAB-HRMS m/z
calcd for C17H30N5O5 (M - H+) 384.2247, found 384.2233.
(()-tr a n s-3-Azido-1-(ter t-bu toxycar bon yl)-4-(ter t-bu tyl)-
2-a zetid in on e (8d ). Flash chromatography (10:1 hexanes/
EtOAc) produced the title compound as a clear oil as an
inseparable mixture (18:1 trans/ cis) of isomers (75%): 1H
NMR (CDCl3) δ 4.45 (d, J ) 2.70 Hz, 1H, cis isomer), 4.34 (d,
J ) 3.00 Hz, 1H, trans isomer), 3.84 (d, J ) 2.70 Hz, 1H, cis
isomer), 3.64 (d, J ) 3.00 Hz, 1H, trans isomer), 1.51 (s, 9H),
1.03 (s, 9H); 13C NMR (CDCl3) δ (trans isomer) 162.78, 148.63,
84.30, 69.16, 64.99, 32.86, 28.08, 26.44; (cis isomer) 72.59,
59.42, 33.62, 26.34; IR (neat) 2112, 1814, 1734 cm-1; FAB-
HRMS m/z calcd for C12H21N4O3 (M - H+) 269.1614, found
269.1613.
(()-tr a n s-3-Azido-1-(ter t-bu toxycar bon yl)-4-(1-adam an -
tyl)-2-a zetid in on e (8e). Filtration through a plug of silica
(10:1 hexanes/EtOAc) provided the title compound as a clear
oil (88%): 1H NMR (CDCl3) δ 4.50 (d, J ) 2.40 Hz, 1H), 3.51
(d, J ) 2.70 Hz, 1H), 2.05 (br s, 3H), 1.67 (m, 12H), 1.54 (s,
9H); 13C NMR (CDCl3) δ 162.88, 148.93, 84.30, 69.45, 63.39,
38.69, 36.76, 34.50, 28.17, 27.99; IR (neat) 2110, 1811, 1733
cm-1; FAB-HRMS m/z calcd for C18H26N4O3 (M - H+) 347.2083,
found 347.2104.
(()-tr a n s-3-Azid o-1-(ter t-bu toxyca r bon yl)-4-(2-p h en yl-
1-eth yl)-2-a zetid in on e (8f). Filtration through a plug of silica
(10:1 hexanes/EtOAc) provided the title compound as a clear
oil (59%): 1H NMR (CDCl3) δ 7.32 (m, 2H), 7.22 (m, 3H), 4.12
(d, J ) 2.70 Hz, 1H), 3.77 (dt, J 1 ) 9.80 Hz, J 2 ) 2.92 Hz, 1H),
2.74 (m, 2H), 2.55 (m, 1H), 1.92 (dd, J 1 ) 13.80 Hz, J 2 ) 7.20
Hz, 1H), 1.87 (dd, J 1 ) 13.95 Hz, J 2 ) 7.35 Hz, 1H), 1.52 (s,
9H); 13C NMR (CDCl3) δ 161.76, 147.83, 140.02, 128.89, 128.48,
126.73, 84.38, 68.31, 59.82, 32.85, 31.54, 28.14; IR (neat) 2111,
1814, 1727 cm-1; FAB-HRMS m/z calcd for C16H21N4O3 (M -
H+) 317.1614, found 317.1588.
Gen er a l P r oced u r e for th e Syn th esis of Differ en tia ted
Dip ep tid es. To the N1-Boc-â-lactam and glycine methyl ester
hydrochloride (2.5 equiv) suspended in dry DMF under Ar was
added diisopropylethylamine (2.5 equiv) followed by sodium
azide (10-15 mol %). The reaction was stirred at room
temperature until judged complete by TLC and then diluted
with EtOAc (40 mL). The solution was then washed with water
(3×) and brine, dried over Na2SO4, filtered, and evaporated.
The residue was then filtered through a plug of silica to give
the title compounds.
(()-(R,R)-Met h ylglycin e-2-a zid o-3-N-(ter t-b u t oxyca r -
bon yl)-4,4-d im eth ylp en ta m id e (9d ). Flash chromatography
(gradient 7:1 to 4:1 hexanes/EtOAc) produced the title com-
pound as a white solid (81%): mp 105-106 °C; 1H NMR
(CDCl3) δ 7.02 (s, 1H), 5.58 (d, J ) 9.60 Hz, 1H), 4.05 (m, 2H),
3.84 (m, 1H), 3.77 (s, 3H), 1.43 (s, 9H), 0.98 (s, 9H); 13C NMR
(CDCl3) δ 169.86, 169.07, 156.20, 79.74, 62.77, 61.62, 52.70,
41.27, 35.16, 28.51, 26.97; IR (KBr) 2102, 1756, 1715 cm-1
;
FAB-HRMS m/z calcd for C15H28N5O5 (M - H+) 358.2090,
found 358.2085.
(()-(R,R)-Meth ylglycin e-2-a zid o-3-(1-a d a m a n tyl)-3-N-
(ter t-bu toxyca r bon yl)p r op a m id e (9e). Filtration through
a plug of silica (2:1 hexanes/EtOAc) provided the title com-
pound as a white solid (72%): mp 139-140 °C; 1H NMR
(CDCl3) δ 6.82 (m, 1H), 5.45 (d, J ) 10.50 Hz, 1H), 4.11 (dd,
J 1 ) 18.00 Hz, J 2 ) 5.70 Hz, 1H), 4.11 (dd, J 1 ) 19.05 Hz, J 2
) 4.65 Hz, 1H), 3.78 (s, 3H), 3.70 (dd, J 1 ) 10.50 Hz, J 2
)
3.00 Hz, 1H), 2.00 (as, 3H), 1.63 (m, 12H), 1.44 (s, 9H); 13C
NMR (CDCl3) δ 169.82, 169.04, 156.29, 79.72, 77.43, 62.42,
61.20, 52.76, 41.31, 38.94, 36.87, 28.57, 28.41; IR (KBr) 3360,
3294, 2112, 1756, 1684, 1657 cm-1; FAB-HRMS m/z calcd for
C
21H33N5O5 (M - H+) 436.2560, found 436.2555.
(()-(R,R)-Met h ylglycin e-2-a zid o-3-N-(ter t-b u t oxyca r -
bon yl)-5-p h en ylp en ta m id e (9f). Filtration through a plug
of silica (1:1 hexanes/EtOAc) provided the title compound as
a white solid (86%): mp 111-112 °C; 1H NMR (CDCl3) δ 7.28
(m, 2H), 7.18 (m, 3H), 6.82 (m, 1H), 4.90 (d, J ) 8.40 Hz, 1H),
4.33 (as, 1H), 4.18 (m, 1H), 4.00 (dd, J 1 ) 18.15 Hz, J 2 ) 5.25
Hz, 1H), 3.96 (dd, J 1 ) 18.60 Hz, J 2 ) 4.50 Hz, 1H), 3.74 (s,
3H), 2.72 (m, 1H), 2.00 (m, 1H), 1.78 (m, 2H), 1.47 (s, 9H); 13
C
NMR (CDCl3) δ 169.98, 167.76, 155.54, 141.24, 128.68, 128.60,
126.31, 80.21, 66.66, 53.32, 52.71, 41.24, 32.62, 32.15, 28.53;
IR (neat) 3373, 3279, 2095, 1751, 1687, 1665 cm-1; FAB-HRMS
m/z calcd for C19H28N5O5 (M - H+) 406.2090, found 406.2077.
8-(N-Ben zyloxyca r bon yl)-3-oxom eth ylocta n oa te (11).
To carboxylic acid 10 (7.917 g, 29.8 mmol) dissolved in dry
THF cooled to 0 °C with an ice bath under an argon atmo-
sphere was added CDI (5.83 g, 36.0 mmol) in several portions
over 10 min. The resulting solution was stirred at 0 °C for 1
h. In a separate flask, monomethyl malonate (3.892 g, 32.9
mmol) was dissolved in dry THF under argon and cooled to
-78 °C. To this solution was added slowly a heptane solution
of Bu2Mg (16.6 mL, 1.0M, 33.2 mmol). After several minutes
the -78 °C bath was removed and the resulting slurry stirred
at room temperature for 1 h. After this time, the acyl imidazole
solution was added via cannula to the magnesium salt and
the resulting mixture stirred at room temperature for 23 h.
(()-(R,R)-Met h ylglycin e-2-a zid o-3-N-(ter t-b u t oxyca r -
bon yl)tetr a d eca m id e (9a ). Filtration through a plug of silica
(4:1 hexanes/EtOAc) gave the title compound as a white solid
(84%). An analytical sample was obtained by recrystallization
from diethyl ether/hexanes: mp 75.5-77.0 °C; 1H NMR
(CDCl3) δ 6.85 (m, 1H), 4.78 (d, J ) 8.40 Hz, 1H), 4.38 (s, 1H),
4.13 (dd, J 1 ) 18.00 Hz, J 2 ) 5.70 Hz, 2H), 3.99 (dd, J 1 ) 18.15
Hz, J 2 ) 4.65 Hz, 1H), 3.77 (s, 2H) 1.46 (br s, 12H), 1.25 (m,
17H); 13C NMR (CDCl3) δ 170.04, 167.87, 155.58, 80.09, 66.74,
40 J . Org. Chem., Vol. 68, No. 1, 2003