Enantioselective Synthesis of R-Amino Acids
The solvent was removed by rotary evaporator and the residue
chromatographed (gradient 4:1 hexanes/EtOAc to 100% EtOAc)
to give the title compound as a yellow oil (144 mg, 79% overall,
95% based on recovered 19) plus recovered 19 (22 mg). 1H
NMR (CDCl3) δ 3.72 (d, J ) 2.40 Hz, 1H), 3.25 (dt, J ) 8.70
Hz, J ) 3.00 Hz, 1H), 1.81 (m, 1H), 1.27 (bs, 19H), 1.13 (s,
9H), 0.953 (s, 9H), 0.88 (t, J ) 6.75 Hz, 3H), 0.22 (d, J ) 2.70
Hz, 6H); 13C NMR (CDCl3) δ 176.85, 67.32, 61.85, 50.95, 35.16,
32.10, 30.19, 29.92, 29.80, 29.68, 29.51, 26.47, 25.35, 22.87,
18.52, 14.30, -4.98, -5.49; IR (neat): 1743 cm-1; FAB-
HRMS: calculated for C24H51N2OSi (M - H+) 411.3771, found
411.3778.
(()-tr a n s-3-(N,N-(1,1-Dim et h ylet h yl)ch lor oa m in o)-1-
(d im et h yl(1,1-d im et h ylet h yl)silyl)-4-u n d ecyl-2-a zet id i-
n on e (22). To a solution of compound 20c (32 mg, 0.078 mmol)
in dry THF (1 mL) at -78 °C was added tert-butyl hypochlorite
(10.5 µL, 0.093 mmol), and the resulting solution was stirred
for 30 min. The solvent was then removed with a rotary
evaporator and the resulting residue filtered through a plug
of silica (7:1 hexanes/EtOAc) to give the title compound as a
clear oil (23 mg, 66%). 1H NMR (CDCl3) δ 4.25 (d, J ) 2.70
Hz, 1H), 3.70 (dt, J ) 9.20 Hz, J ) 3.07 Hz, 1H), 1.85 (m, 1H)
1.49 (m, 3H), 1.32 (s, 9H), 1.27 (bs, 16H) 0.98 (s, 9H), 0.89 (m,
3H), 0.28 (s, 3H), 0.22 (s, 3H); 13C NMR (CDCl3) δ 171.82,
62.87, 56.33, 34.61, 32.12, 29.99, 29.81, 29.72, 29.68, 29.55,
28.12, 26.42, 25.45, 22.89, 18.78, 14.33, -5.02, -5.47; IR
(neat): 1750 cm-1; FAB-HRMS: calculated for C24H49ClN2-
OSi (M - H+) 445.3384, found 445.3415.
1H), 0.65 (m, 2H), 0.33 (m, 2H); 13C NMR (CDCl3) δ 164.91,
69.80, 60.81, 12.92, 3.16, 2.47; IR (KBr): 3219, 2102, 1755
cm-1; FAB-HRMS calculated for C6H9N4O (M - H+) 153.0776
found 153.0785.
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-Azid o-1-
ben zyl-2-a zetid in on es. CsF (10-12 equiv) was suspended
in dry DMF (1 mL) under Ar, and to this suspension was added
BnBr (2.5 equiv). To this flask was then added a solution of
the 3-azido â-lactam in dry DMF (total substrate concentra-
tions were kept at 0.1 M) by syringe pump over several hours.
During this addition, and for several hours after it was
completed, the reaction was stirred vigorously. When TLC
analysis indicated complete consumption of the starting lac-
tam, the reaction was diluted with EtOAc and washed with
water (4×) followed by brine. The resulting organic phase was
dried over sodium sulfate, filtered, and concentrated. The
residue was then purified by flash chromatography as de-
scribed to give the title compounds.
(()-3-Azid o-1-b en zyl-4-u n d ecyl-2-a zet id in on e (27a ).
Flash chromatography (gradient 10:1 to 7:1 hexanes/EtOAc)
provided the title compound (76 mg, 66%) as a light yellow
oil. 1H NMR (CDCl3) δ 7.35 (m, 3H), 7.25 (m, 2H), 4.68 (d, J )
15.00 Hz), 4.182 (m, 1H), 4.09 (d, J ) 15.30 Hz), 3.33 (m, 1H),
1.69 (m, 1H), 1.33 (m, 19H), 0.88 (m, 3H); 13C NMR (CDCl3) δ
164.02, 135.25, 129.16, 128.36, 128.22, 68.95, 60.10, 44.82,
32.11, 31.20, 29.77, 29.63, 29.57, 29.53, 29.50, 25.52, 22.87,
14.32; IR (neat): 2106, 1767 cm-1; FAB-HRMS: calculated
for C21H33N4O (M - H+) 357.2654, found 357.2672.
(()-1-(ter t-Bu toxyca r bon yl)-3-(ter t-Bu tylim in o)-4-u n -
d ecyl-2-a zetid in on e (25). Compound 20a (106 mg, 0.267
mmol) was dissolved in dry THF (2.5 mL) under nitrogen and
cooled to -78 °C. To the cooled solution was then added tert-
butyl hypochlorite (45 µL, 0.398 mmol), and the resulting
solution was stirred for 20 min at -78 °C and then warmed
to room temperature. The solvent was removed with a rotary
evaporator and the residue redissolved in dry acetonitrile
under nitrogen. The resulting solution was cooled to 0 °C. To
the cooled solution was then added DBU (44 mL, 0.294 mmol),
and the solution was stirred for 1 h. The solvent was then
removed with a rotary evaporator and the residual material
filtered through a plug of silica (10:1 hexanes/EtOAc) to give
the title compound (60 mg, 57%) as a clear oil. 1H NMR (CDCl3)
δ 4.35 (m, 1H), 1.88 (m, 2H), 1.57 (s, 9H), 1.40 (s, 9H), 1.29
(bs, 18H) 0.88 (m, 3H); 13C NMR (CDCl3) δ 161.06, 155.95,
149.01, 83.92, 64.43, 58.96, 32.11, 30.32, 30.10, 29.81, 29.69,
29.65, 29.54, 29.51, 18.24; IR (neat): 1805, 1793 cm-1; FAB-
HRMS: calculated for C23H43N2O3 (M-H+) 395.3274, found
395.3284.
Gen er a l P r oced u r e for th e P r ep a r a tion of tr a n s-3-
Azid o-â-La cta m s. To the N-tosyloxy â-lactam dissolved in dry
acetonitrile under an inert atmosphere was added TMSN3 (2
equiv) followed by diisopropylethylamine (3 equiv). The result-
ing mixture was stirred at room temperature until all of the
starting material was consumed as determined by TLC
analysis (2-5 days). The solution was then concentrated with
a rotary evaporator and the residue purified by flash chroma-
tography to yield the desired title compounds.
(()-tr a n s-3-Azid o-4-u n d ecyl-2-a zetid in on e (26a ). Flash
chromatography (gradient 10:1 to 4:1 hexanes/EtOAc) yielded
the title compound as a yellow oil (178 mg, 65%). 1H NMR
(CDCl3) δ 6.60 (s, 1H), 4.16 (s, 1H), 3.52 (dt, J ) 9.70 Hz, J )
3.37 Hz, 1H), 1.67 (m, 2H), 1.30 (m, 18H), 0.88 (m, 3H); 13C
NMR (CDCl3) δ 164.89, 69.87, 57.31, 33.67, 32.08, 29.7629.65,
29.58, 29.50, 29.39, 26.17, 22.85, 14.28; IR (neat) 3256, 2108,
1770 cm-1; FAB-HRMS: calculated for C14H27N4O (M - H+)
267.2185, found 267.2174.
(()-tr a n s-3-Azid o-4-cyclop r op yl-2-a zetid in on e (26b).
Flash chromatography (4:1 hexanes/EtOAc) yielded the title
compound as a crystalline solid (206 mg, 66%). Analytically
pure material was obtained by recrystallization from Et2O/
hexanes: mp ) 50.5-51.0 °C; 1H NMR (CDCl3) δ 6.58 (s, 1H),
4.34 (m, 1H), 3.11 (dd, J ) 7.95 Hz, J ) 1.95 Hz, 1H), 1.02 (m,
(()-tr a n s-3-Azid o-1-(p -m et h oxyb en zyl)-4-u n d ecyl-2-
a zetid in on e (27a ′). Flash chromatography (7:1 hexanes/
EtOAc) gave the title compound as a yellow oil (49 mg, 36%).
1H NMR (CDCl3) δ 7.17 (m, 2H), 6.88 (m, 2H), 4.62 (d, J )
15.00 Hz, 1H), 4.15 (d, J ) 1.50 Hz, 1H), 4.02 (d, J ) 15.00
Hz, 1H), 3.81 (s, 3H), 3.31 (m, 1H), 1.69 (m, 2H), 1.33 (m, 18H),
0.88 (m, 3H); 13C NMR (CDCl3) δ 163.92, 159.56, 128.69,
127.22, 114.52, 68.83, 59.88, 55.50, 44.31, 32.10, 31.22, 29.78,
29.65, 29.59, 29.52, 25.52, 22.88, 14.31; IR (neat): 2105, 1764
cm-1; FAB-HRMS: calculated for C22H35N4O2S (M - H+)
387.2760 found 387.2755.
(()-tr a n s-3-Azid o-1-ben zyl-4-cyclop r op yl-2-a zetid in o-
n e (27b). Flash chromatography (gradient 2:1 to 1:1 hexanes/
EtOAc) provided the title compound as a yellow oil (42 mg,
1
64%). H NMR (CDCl3) δ 7.32 (m, 5H), 4.71 (d, J ) 15.00 Hz,
1H), 4.36 (d, J ) 1.5 Hz, 1H), 4.18 (d, J ) 15.00 Hz, 1H), 2.64
(dd, J ) 9.45 Hz, J ) 1.95 Hz), 0.76 (m, 1H), 0.58 (m, 2H),
0.19 (m, 1H), 0.07 (m, 1H); 13C NMR (CDCl3) δ 163.89, 135.40,
129.02, 128.42, 128.09, 69.15, 65.01, 44.76, 11.14, 4.60, 1.56;
IR (neat): 2106 cm-1, 1770 cm-1; FAB-HRMS calculated for
C
13H15N4O (M - H+) 243.1246 found 243.1255.
(()-1-Ben zyl-3-oxo-4-u n d ecyl-2-a zetid in on e (28a ). A 10
mL round-bottom flask was charged with nitrogen, compound
27a (50 mg, 0.140 mmol), dry, deoxygenated THF (1.4 mL),
and 10% Pd/C (12 mg) in that order. The flask was then placed
under a hydrogen atmosphere (1 atm) and stirred vigorously.
Monitoring by TLC showed complete consumption of compound
27a after 20 min. The flask was then purged with nitrogen
for several minutes, and the catalyst was removed from the
solution by filtering through a disposable pipet containing a
cotton plug. (The subsequent reactions could also be carried
out without first removing the catalyst. However, later stage
purification was more convenient if the catalyst was removed
earlier.) The cotton plug was washed with CH2Cl2 (4 mL), and
all of the organic solvents were combined and removed with a
rotary evaporator. The residue was then redissolved in dry
THF (1.4 mL) under a nitrogen atmosphere and cooled to -78
°C. To the cooled solution was then added tert-butyl hypochlo-
rite (18 µL, 0.159 mmol), and the resulting solution was stirred
for 20 min. To the flask was then added DBU (25 µL, 0.167
mmol), and the flask was allowed to slowly warm to room
temperature. After 1.5 h, a saturated aqueous oxalic acid
solution (0.7 mL) was added and the reaction stirred for an
additional 10 min. The reaction was then diluted with EtOAc
J . Org. Chem, Vol. 68, No. 1, 2003 33