9890 J. Am. Chem. Soc., Vol. 118, No. 41, 1996
Hanessian and Rozema
THIO), m/e (rel intensity) 356.3 (MH+, 12), 298.5 (35), 181.1 (50),
156.2 (100), 114.9 (31); HRMS calculated for C18H34O4NSi 356.2257,
found 356.2248. For 14: mp 124-126 °C (hexane); [R]D -17.5° (c
1.18, CHCl3); IR (CHCl3) 3470 (NH), 2980, 2930, 1760 (â-lactam CO),
and either saturated aqueous ammonium chloride or D2O as specified.
Integrating the disappearance of the resonance at 3.58 ppm (H R to
1
OMe) in the H NMR spectra (300 MHz) of crude reaction mixtures
gave the values in Table 3. In entries 3 and 4, the butyllithium was
added to the lithium enolate at -78 °C and stirred for an additional
hour before the addition of the zinc bromide.
1
1720 (cHex CO), 1470, 1140 cm-1; H NMR (300 MHz, CDCl3) δ
6.07 (s, 1H, NH), 4.19-4.08 (m, 1H, TBSOCH), 3.82-3.76 (m, 1H,
ΜeOCH), 3.69 (dd, 1H, J ) 2.1, 9.7 Hz, â-lactam R to N), 3.46 (s,
3H, CH3O), 2.71 (dd, 1H, J ) 1.4, 5.7 Hz, â-lactam R to CO), 2.47-
2.35 (m, 2H), 2.17-2.10 (m, 1H), 2.02-1.96 (m, 1H), 1.80-1.57 (m,
2H), 1.44-1.27 (m, 1H), 1.24 (d, 3H, J ) 6.2 Hz, CH3CHOTBS),
0.89 (s, 9H, t-Bu), 0.09 (s, 3H, CH3Si), 0.07 (s, 3H, CH3Si); 13C NMR
(75.5MHz, CDCl3) δ 209.2, 167.6, 84.1, 65.6, 63.4, 57.8, 55.0, 50.2,
34.4, 31.4, 25.7, 22.8, 17.8, -4.5, -4.8; MS (FAB, THIO), m/e (rel
intensity) 356.2 (MH+, 14), 298.4 (25), 181.2 (18), 156.2 (100); HRMS
calcd for C18H34O4NSi: 356.2257, found 356.2252.
Benzyl {(3S,4R)-3-[(1R)-1-((tert-butyldimethylsilyl)oxy)ethyl]-4-
[(1S,3S)-3-methoxy-2-oxocyclohexyl]-2-oxoazetidin-1-yloxoacetate
(15). To a solution of 4 (355 mg, 1.0 mmol) in CH2Cl2 (2 mL), was
added a solution of benzyl oxalyl chloride (297 mg, 1.5 mmol) in CH2-
Cl2 (2 mL) and pyridine (160 µl, 2.0 mmol) at 0 °C. The reaction was
warmed to room temperature, stirred for 3 h, poured into water (20
mL), and extracted three times with CH2Cl2 (25 mL). The combined
organic layers were dried over MgSO4, filtered, and concentrated.
Purification by chromatography (hexanes-ethyl acetate, 4:1) afforded
the desired product 15 (500 mg, 97%) as a colorless oil; [R]D -42.3°
(c 1.40, CHCl3); IR (CHCl3) 2940, 2880, 1820 (CO), 1760 (CO), 1740
(CO), 1700 (CO), 1400, 1110 cm-1; MS (FAB), m/e (rel intensity)
518.4 (MH+, 15), 486.4 (43), 460.3 (100), 159.2 (72); HRMS calcd
for C27H40O7NSi 518.2574, found 518.2592.
Preparation of 4 from the Epimerization of a 1:1 Mixture of 4
and 13. Following procedures described above, a ca. 1:1 mixture of
4 and 13 (1.47 g, 69%) was obtained from 7 (1.34 g, 6.3 mmol) and
6 (1.72 g, 6.0 mmol) after chromatography (hexanes-ethyl acetate,
4:1 to 0:1) to remove 14 (235 mg, 11%). The 1:1 mixture of 4 and 13
was subjected to epimerization as follows. To a solution of LDA
prepared by adding n-BuLi (3.4 mL, 8.5 mmol, 2.5 M in hexanes) to
a solution of diisopropylamine (1.3 mL, 9.3 mmol) in THF (10 mL) at
0 °C and stirring for 15 min, was added dropwise a solution of 4 and
13 (ca. 1:1, 1.0 g, 2.8 mmol) in THF (10 mL) over 15 min at -10 °C.
After an additional 10 min, a solution of ZnBr2, prepared by refluxing
a solution of 1,2-dibromoethane (0.26 mL, 3.0 mmol) in THF (10 mL)
over zinc powder (390 mg, 6.0 mmol) for 2 h, was added via cannula,
and the reaction was allowed to warm to 0 °C over 10 min. Diethyl
malonate (2.2 mL, 14 mmol) was added, and the reaction was warmed
to room temperature over 30 min and stirred for an addition 10-15
min (premature workup leads to lower ratios). The reaction mixture
was then poured into saturated aqueous NH4Cl (50 mL) and extracted
twice with ethyl acetate (100 mL). The aqueous phase was made acidic
by the addition of 10% HCl (10 mL) and extracted with ethyl acetate
(100 mL). The combined organic layers were washed with brine (50
mL), dried over MgSO4, and filtered, and the solvents were removed.
Recrystallization of the residue from hexanes afforded 4 as a white
crystalline solid mp 124-126 °C (510 mg, 51%). Chromatography of
the mother liquor (hexane-ethyl acetate, 2:1) afforded an additional
quantity (210 mg, 21%) of 4 as a white crystalline solid (total yield
Benzyl (4S,8S,9R,10S)-4-Methoxy-10-[(1R)-1-((tert-butyldimeth-
ylsilyl)oxy)ethyl]-11-oxo-1-azatricyclo[7.2.0.03,8]undec-2-ene-2-car-
boxylate (16). To a solution of 15 (485 mg, 0.94 mmol) in xylene (5
mL) was added triethyl phosphite (0.8 mL, 4.7 mmol). The resulting
solution was heated to 155-160 °C for 14 h and then cooled to room
temperature. The reaction mixture was then poured onto a silica gel
column and eluted with hexanes to remove the xylene, followed by a
hexanes-ethyl acetate (4:1) eluant to obtain the desired product 16
(378 mg, 83%) as a colorless oil: [R]D 50.5° (c 1.26, CHCl3); IR
(CHCl3) 2940, 2860, 1775 (â lactam CO), 1740 (ester CO), 1670, 1290,
1140 cm-1 1H NMR (300 MHz, CDCl3) δ 7.47-7.28 (m, 5H,
;
aromatic), 5.35 (d, 1H, J ) 12.6 Hz, benzylic H), 5.23 (d, 1H, J )
12.6, benzylic H), 4.96 (apparent t, 1H, MeOCH), 4.27-4.21 (m, 1H,
TBSOCH ), 4.16 (dd, 1H, J ) 3.3, 10.5 Hz, â lactam R to N), 3.50-
3.15 (m, 2H, HC8 and HC9), 3.24 (s, 3H, CH3O), 2.10-2.03 (m, 1H,
cHex), 1.88-1.81 (m, 2H, cHex), 1.69-1.27 (m, 3H, cHex), 1.24 (d,
3H, J ) 6.2 Hz, CH3CHOTBS), 0.88 (s, 9H, tBuSi), 0.08 (s, 6H, Me2-
Si); 13C NMR (75.5MHz, CDCl3) δ 175.6, 160.9, 148.5, 135.4, 128.3,
128.0, 127.8, 126.3, 72.1, 66.6, 65.9, 61.0, 56.0, 54.8, 43.8, 32.3, 30.6,
25.6, 22.3, 20.2, 17.8, -4.3, -5.0 ppm; MS (FAB), m/e (rel intensity)
486.3 (MH+, 40), 428.2 (65), 286.1 (46), 159.1 (100); HRMS calcd
for C27H40O5NSi 486.2676, found 486.2716.
1
72%, H NMR of crude reaction mixture showed an R-â MeO ratio
of 21/1).
Benzyl (4S,8S,9R,10S)-4-Methoxy-10-[(1R)-1-hydroxyethyl]-11-
oxo-1-azatricyclo[7.2.0.03,8]undec-2-ene-2-carboxylate (17). To a
solution of 16 (429 mg, 0.88 mmol) in THF (10 mL) were added acetic
acid (230 µL, 2.7 mmol) and a solution of tetrabutylammonium fluoride
(3 mL, 3 mmol, 300 MHz1 M in THF). The reaction mixture was
stirred for 4 days at room temperature and then diluted with ethyl ether
(300 mL). The organic layer was washed with saturated aqueous
NaHCO3 (50 mL), saturated aqueousNH4Cl (2 × 50 mL), and brine
(50 mL), dried over MgSO4, and filtered. After removal of the solvents,
the crude product was purified by chromatography (hexanes-ethyl
acetate, 1:1) to afford the desired product 15 (288 mg, 88%) as colorless
oil: [R]D +66.8° (c 2.82, CHCl3); IR (CHCl3) 2940, 2880, 1770 (CO,
General Procedure for the Protonation of the Lithium Enolates
of 4 and/or 13. To a solution of LDA (0.38 mL, ca. 0.085 mmol),
prepared by adding n-BuLi (0.4 mL, 1 mmol, 2.5 M in hexanes) to a
solution of diisopropylamine (0.15 mL, 1.1 mmol) in THF (4 mL) at
0 °C and stirring for 15 min, was added dropwise over 1 min a solution
of a mixture of 4 and 13 (ca 1:1, 10 mg, 0.028 mmol) in THF (1 mL).
After stirring for 30 min, a solution of the proton source (5 equiv) in
THF was added all at once. The solution was warmed to room
temperature and then poured into ethyl acetate (50 mL) and saturated
aqueous ammonium chloride (10 mL). The layers were separated, and
the organic layer was washed with brine, dried over Na2SO4, and
concentrated in vacuo. Integration of the methoxy CH3 resonances (â-
methoxy at 3.29 ppm, R-methoxy at 3.46 ppm) in the 1H NMR spectra
of the crude reaction mixtures gave the ratios listed in Table 1.
â-lactam), 1720 (CO, benzyl ester), 1640, 1380, 1090 cm-1 1H NMR
.
(300 MHz, CDCl3) δ 7.46-7.27 (m, 5H, aromatic), 5.37 (d, 1H, J )
12.5 Hz, benzylic), 5.21 (d, 1H, J ) 12.5 Hz, benzylic), 4.94 (apparent
t, 1H, MeOCH), 4.26-4.22 (m, 1H, HOCH), 4.18 (dd, 1H, J ) 3.2,
10.2 Hz, â lactam R to N), 3.28-3.19 (m, 2H, HC8 and HC9), 3.20 (s,
3H, CH3O), 2.07-2.01 (m, 1H, cHex), 1.90-1.67 (m, 2H, cHex), 1.67-
1.61 (m, 1H, cHex), 1.48-1.26 (m, 2H, cHex), 1.32 (s, 3H, J ) 6.3
Hz, H3CCOH) ppm; 13C NMR (75.5 MHz, CDCl3) δ 175.6, 161.0,
149.4, 135.3, 128.5, 128.2, 128.0, 126.1, 72.3, 66.9, 65.5, 60.4, 56.0,
54.9, 44.0, 32.4, 30.6, 21.5, 20.1 ppm; MS (FAB, NBA), m/e (rel
intensity) 372.2 (MH+, 20), 340.4 (20), 286 (20), 167.2 (22), 149.1
(100); HRMS calcd for C21H26O5N 372.18109, found 372.1824.
(4S,8S,9R,10S)-4-Methoxy-10-[(1R)-1-hydroxyethyl]-11-oxo-1-
azatricyclo [7.2.0.03,8]undec-2-ene-2-carboxylic Acid Amidinium Salt
(19). To a solution of 17 (241 mg, 0.65 mmol) in 1,4-dioxane (4 mL)
were added 10% palladium-on-carbon (200 mg) and 3,3,6,9,9-pentam-
ethyl-2,10-diazabicyclo[4.4.0]dec-1-ene (146 µL, 0.65 mmol). The
resulting mixture was stirred under 1 atm of hydrogen for 1 h at room
General Procedure for the Protonation or Deuteration of the
Zinc Enolate of 4 and/or 13. To a solution of the lithium enolate
prepared as above in THF was added at -78 °C a solution of zinc
bromide (0.14 mL, 0.028 mmol, 0.2 M in THF). Stock solutions of
0.2 M zinc bromide were prepared by refluxing 1,2-dibromoethane (172
µL, 2.0 mmol) over zinc powder (320 mg, 5 mmol) for 2 h and diluting
to a total volume of 10 mL with THF. The reaction mixture was
warmed to 0 °C, and the proton source (5 equiv) was added either neat
if it was a liquid or as a solution in THF if a solid. The reaction was
then warmed to room temperature and stirred for approximately 30
1
min. Workup was as described above, and H NMR analysis of the
crude mixtures gave the ratios listed in Tables 2 and 4. Deuteration
experiments were conducted in a similar manner. The additives were
added to the zinc enolate at 0 °C, and the solution was stirred at room
temperature for the specified times and workedup with ethyl acetate