C4,C4′-Bis-â-lactam-Fused Bis-γ-lactam Rearrangement
J . Org. Chem., Vol. 61, No. 26, 1996 9161
J ) 7.2 Hz), 5.88 (d, 2H, J ) 3.3 Hz), 7.22-7.30 (m, 10H). 13C
NMR (DMSO-d6, 100 °C): δ 168.3, 164.3, 140.1, 128.0, 126.9,
126.1, 73.3, 56.8, 53.7, 19.6, 18.8. IR (CHCl3): ν 1765, 1750.
Anal. Calcd for C26H28N2O6: C, 67.24; H, 6.03; N, 6.03.
Found: C, 67.28; H, 6.00; N, 6.07.
3.97 (dd, 1H, J 1 ) 5.4 Hz, J 2 ) 7.5 Hz), 4.45-4.51 (m, 2H),
4.63 (d, 1H, J ) 12.0 Hz), 4.70 (d, 1H, J ) 6.9 Hz), 4.76-4.81
(m, 2H), 5.99 (d, 1H, J ) 4.8 Hz), 6.78 (m, 2H), 6.96 (d, 2H, J
) 8.7 Hz), 7.23-7.35 (m, 10H). 13C NMR: δ 168.4, 165.7,
164.9, 157.4, 140.7, 135.9, 134.2, 129.4, 128.8, 128.7, 128.5,
128.3, 127.6, 120.8, 114.5, 79.8, 74.3, 73.1, 57.6, 56.3, 55.5, 45.9,
20.5. IR (CHCl3): ν 1755, 1680. Anal. Calcd for C29H28N2O6:
C, 69.59; H, 5.64; N, 5.60. Found: C, 69.70; H, 5.77; N, 5.58.
(+)-(3R ,4S ,4′S ,3′R )-1-(p -An isyl)-4-[1-b e n zyl-3-(b e n z-
yloxy)-2-oxoazetidin -4-yl]-3-(ben zyloxy)-2-azetidin on e (1i).
Meth od B. Reaction time: 3 h. Yield: 0.46 g (85%). Color-
less oil. [R]D: +35.92 (c 1.35). 1H NMR: δ 3.25 (d, 1H, J )
14.7 Hz), 3.78 (d, 1H, J ) 14.7 Hz), 3.79 (s, 3H), 3.90 (dd, 1H,
J 1 ) 5.4 Hz, J 2 ) 7.5 Hz), 4.61-4.69 (m, 4H), 4.80 (d, 1H, J )
5.4 Hz), 4.80 (d, 1H, J ) 12.0 Hz), 4.89 (d, 1H, J ) 12.0 Hz),
6.79-6.83 (m, 2H), 6.90 (d, 2H, J ) 8.7 Hz), 7.18-7.39 (m, 15H).
13C NMR: δ 168.2, 165.0, 157.0, 136.7, 136.5, 134.6, 130.0,
128.7, 128.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 121.5,
120.2, 114.5, 81.6, 80.9, 73.2, 73.1, 57.3, 56.2, 55.4, 45.5. IR
(CHCl3): ν 1750. Anal. Calcd for C34H32N2O5: C, 74.43; H,
5.88; N, 5.11. Found: C, 74.58; H, 5.92; N, 5.19.
(3S *,4R *,4′S *,3′R *)-1-(p -An is y l)-4-[1-(p -a n is y l)-3-
(ben zyloxy)-2-oxoa zetid in -4-yl]-3-isop r op yl-2-a zetid in o-
n e (1j). Meth od B. Reaction time: 2 h. Yield: 0.35 g (70%).
White solid. Mp: 143-145 °C (EtOAc/hexanes). 1H NMR: δ
0.90 (d, 3H, J ) 6.6 Hz), 0.93 (d, 3H, J ) 6.6 Hz), 2.00-2.15
(m, 1H), 3.22 (dd, 1H, J 1 ) 2.1 Hz, J 2 ) 6.0 Hz), 3.70 (s, 6H),
4.35 (dd, 1H, J 1 ) 2.1 Hz, J 2 ) 6.0 Hz), 4.57 (t, 1H, J ) 6.0
Hz), 4.76 (d, 1H, J ) 11.7 Hz), 4.83 (d, 1H, J ) 11.7 Hz), 4.85
(d, 1H, J ) 5.7 Hz), 6.65 (d, 2H, J ) 9.0 Hz), 7.06-7.37 (m,
9H). 13C NMR: δ 166.4, 164.7, 156.3, 155.9, 136.2, 130.4,
129.9, 128.4, 128.2, 128.0, 118.9, 118.7, 114.1, 114.0, 80.7, 73.5,
59.9, 57.9, 55.3, 55.2, 54.7, 27.8, 20.6, 18.8. IR (KBr): ν 1745.
MS: m/e 500 (M•+), 351, 309, 244, 190, 149, 134, 91 (parent).
Anal. Calcd for C30H32N2O5: C, 71.98; H, 6.44; N, 5.60.
Found: C, 72.15; H, 6.55; N, 5.55.
(3R *,4R *,4′S *,3′R *)-1-(p -An is y l)-4-[1-(p -a n is y l)-3-
(ben zyloxy)-2-oxoa zetid in -4-yl]-3-isop r op yl-2-a zetid in o-
n e (1k ). Meth od B. Reaction time: 2 h. Yield: 0.42 g (85%).
White solid. Mp: 151-152 °C (EtOAc/hexanes). 1H NMR: δ
0.97 (d, 3H, J ) 6.6 Hz), 1.25 (d, 3H, J ) 6.6 Hz), 2.21 (m,
1H), 3.14 (dd, 1H, J 1 ) 5.7 Hz, J 2 ) 8.7 Hz), 3.57 (s, 3H), 3.58
(s, 3H), 4.53 (dd, 1H, J 1 ) 5.7 Hz, J 2 ) 9.0 Hz), 4.67 (dd, 1H,
J 1 ) 5.7 Hz, J 2 ) 9.0 Hz), 4.75 (d, 1H, J ) 11.4 Hz), 4.81 (d,
1H, J ) 5.4 Hz), 4.99 (d, 1H, J ) 11.4 Hz), 6.39-6.42 (m, 4H),
6.85-7.34 (m, 9H). 13C NMR: δ 167.5, 165.0, 156.4, 156.1,
136.5, 130.6, 130.3, 128.5, 128.3, 128.2, 119.6, 119.0, 113.8,
113.7, 80.7, 73.4, 66.9, 59.2, 56.3, 55.4, 53.3, 25.7, 22.9, 21.0.
IR (KBr): ν 1745. Anal. Calcd for C30H32N2O5: C, 71.98; H,
6.44; N, 5.60. Found: C, 71.78; H, 6.45; N, 5.70.
Syn th esis of (+)-(3R,4S,4′S,3′R)-3,3′-Dih yd r oxy-1,1′-bis-
[(S)-r-p h en yl-eth yl)]-4,4′-bi-2-a zetid in on e (1e). To a solu-
tion of biazetidinone 1b-R (1.0 g, 2.1 mmol) in absolute MeOH
(25 mL) was added NaOMe (0.24 g, 4.3 mmol). The mixture
was stirred under argon for 2 h. Then, the excess NaOMe was
hydrolyzed with water (2 drops), the solvent was partially
evaporated under reduced pressure, and 10 mL of water was
added. The product was extracted with EtOAc and dried
(MgSO4). After filtration and evaporation of the solvent, the
residue was purified by crystalization (EtOAc) to yield 0.65 g
(81%) of compound 1e. White solid. Mp: 155-157 °C. [R]D:
+62.7 (c 1.13, EtOH). 1H NMR: δ 1.71 (d, 6H, J ) 7.2 Hz),
3.67 (d, 2H, J ) 4.5 Hz), 4.53 (q, 2H, J ) 7.2 Hz), 4.73 (s (b),
2H), 6.37 (s (b), 2H), 7.19-7.34 (m, 10H). 13C NMR: δ 169.7,
142.7, 133.7, 128.5, 126.3, 74.2, 57.2, 54.4, 20.6. IR (KBr): ν
3500, 1725. Anal. Calcd for C22H23N2O4: C, 69.64; H, 6.11;
N, 7.38. Found: C, 69.61; H, 6.33; N, 7.48.
3,3′-Bis(ben zyloxy)-1,1′-bis[(S)-r-p h en yleth yl)]-4,4′-bi-
2-a zetid in on es 1c. Meth od A. Reaction time: 3 h. Com-
pound 1c was obtained as a 1.1:1 mixture of diastereomers.
(+)-(3R ,4S ,4′S ,3′R )-3,3′-b is(b e n zy lo xy )-1,1′-b is[(S )-r-
p h en yleth yl)]-4,4′-bi-2-a zetid in on e (1c-r). Yield: 0.18 g
(33%). Yellow oil. [R]D: +2.4 (c 2.0). 1H NMR: δ 1.91 (d, 6H,
J ) 7.2 Hz), 3.60 (d, 2H, J ) 5.1 Hz), 4.47-4.49 (m, 4H), 4.54
(d, 2H, J ) 11.7 Hz), 4.76 (d, 2H, J ) 11.7 Hz), 7.11-7.29 (m,
20H). 13C NMR: δ 168.5, 142.5, 136.4, 128.6, 128.5, 128.4,
128.2, 127.2, 126.5, 80.3, 73.6, 56.6, 55.5, 21.4. IR (CHCl3): ν
1740, 1500, 1450, 1400. Anal. Calcd for C36H36N2O4: C, 77.14;
H, 6.48; N, 4.00. Found: C, 77.26; H, 6.51; N, 4.07. (+)-
(3S,4R,4′R,3′S)-3,3′-bis(ben zyloxy)-1,1′-bis[(S)-r-p h en yl-
eth yl)]-4,4′-bi-2-a zetid in on e (1c-â). Yield: 0.16 g (29%).
Yellow oil. [R]D: +0.3 (c 3.4). 1H NMR: δ 1.35 (d, 6H, J )
7.2 Hz), 3.91 (d, 2H, J ) 5.1 Hz), 4.52 (q, 2H, J ) 7.2 Hz),
4.55 (d, 2H, J ) 5.1 Hz), 4.63 (d, 2H, J ) 11.7 Hz), 4.88 (d,
2H, J ) 11.7 Hz), 7.21-7.34 (m, 20H). 13C NMR: δ 168.3,
140.2, 136.6, 128.6, 128.5, 128.4, 128.3, 127.4, 127.3, 80.7, 73.3,
56.5, 53.5, 18.4. IR (CHCl3): ν 1745. Anal. Calcd for
C36H36N2O4: C, 77.14; H, 6.48; N, 4.00. Found: C, 77.19; H,
6.44; N, 4.03.
3,3′-Dim et h oxy-1,1′-b is[(S)-r-p h en ylet h yl)]-4,4′-2-a ze-
tid in on es 1d . Meth od A. Reaction time: 3 h. Compound
1d was obtained as a 1.1:1 mixture of diastereomers. (+)-
(3R,4S,4′S,3′R)-3,3′-Dim eth oxy-1,1′-bis[(S)-r-ph en yleth yl)]-
4,4′-2-a zetid in on e (1d -r). Yield: 0.16 g (40%). Yellow oil.
[R]D: +2.4 (c 2.0). 1H NMR: δ 1.94 (d, 6H, J ) 7.2 Hz), 3.47
(s, 6H), 3.75 (d, 2H, J ) 5.1 Hz), 4.38 (d, 2H, J ) 5.1 Hz), 4.51
(q, 2H, J ) 7.2 Hz), 7.32 (m, 10H). 13C NMR: δ 168.2, 142.5,
128.5, 127.4, 126.4, 82.4, 59.1, 56.8, 55.1, 21.3. IR (CHCl3): ν
1740. Anal. Calcd for C24H28N2O4: C, 70.57; H, 6.91; N, 6.86.
Found: C, 70.61; H, 6.95; N, 6.84. (+)-(3S,4R,4′R,3′S)-3,3′-
Dim eth oxy-1,1′-bis[(S)-r-p h en yleth yl)]-4,4′-bi-2-a zetid i-
n on e (1d -â). Yield: 0.14 g (36%). White crystalline solid.
Mp: 155-156 °C. [R]D: +72.9 (c 2.51). 1H NMR: δ 1.41 (d,
6H, J ) 6.9 Hz), 3.52 (s, 6H), 3.88 (d, 2H, J ) 4.8 Hz), 4.40 (d,
2H, J ) 4.8 Hz), 4.51 (q, 2H, J ) 7.2 Hz), 7.29 (m, 10H). 13C
NMR: δ 168.1, 140.1, 128.2, 127.3, 127.1, 82.7, 58.9, 56.6, 53.2,
18.3. IR (CHCl3): ν 1740. Anal. Calcd for C24H28N2O4: C,
70.57; H, 6.91; N, 6.86. Found: C, 70.66; H, 6.94; N, 6.88.
(+)-(3R,4S,4′S,3′R)-1-(p-An isyl)-4-[3-acetoxy-1-(p-an isyl)-
2-oxoazetidin -4-yl]-3-(ben zyloxy)-2-azetidin on e (1f). Meth -
od B. Reaction time: 3 h. Yield: 0.39 g (80%). Colorless oil.
[R]D: +10.74 (c 4.70). 1H NMR: δ 2.09 (s, 3H), 3.64 (s, 6H),
4.53 (dd, 1H, J 1 ) 5.4 Hz, J 2 ) 8.1 Hz), 4.77-4.81 (m, 2H),
4.85 (d, 1H, J ) 5.4 Hz), 4.93 (d, 1H, J ) 12.0 Hz), 6.21 (d,
1H, J ) 5.4 Hz), 6.47 (m, 4H), 6.95 (m, 4H), 7.39 (m, 5H). 13C
NMR: δ 168.6, 164.5, 162.1, 156.6, 156.5, 136.2, 129.9, 129.8,
128.8, 128.7, 128.6, 119.4, 119.3, 113.9, 113.8, 80.1, 73.9, 73.3,
56.9, 55.5, 55.4, 20.7. IR (CHCl3): ν 1750, 1680. Anal. Calcd
for C29H28N2O7: C, 67.43; H, 5.46; N, 5.42. Found: C, 67.55;
H, 5.52; N, 5.49.
(+)-(3R,4S,4′S,3′R)-1-(p-An isyl)-4-[1-(p-a n isyl)-2-oxo-3-
p h t h a lim id oa zet id in -4-yl]-3-(b en zyloxy)-2-a zet id in on e
(1g). Meth od B. Reaction time: 15 h. Yield: 80%. White
solid. Mp: 130-132 °C (EtOAc). [R]D: +2.13 (c 0.77) 1H
NMR: δ 3.61 (s, 6H), 4.52 (d, 1H, J ) 5.4 Hz), 4.69 (d, 1H, J
) 11.4 Hz), 4.76 (d, 1H, J ) 11.4 Hz), 4.77 (dd, 1H, J 1 ) 5.4
Hz, J 2 ) 9.3 Hz), 4.90 (dd, 1H, J 1 ) 5.4 Hz, J 2 ) 9.3 Hz), 5.76
(d, 1H, J ) 5.4 Hz), 6.43 (m, 4H), 6.95-7.91 (m, 13H). 13C
NMR: δ 164.4, 161.5, 156.4, 156.3, 135.7, 134.7, 131.3, 129.7,
129.6, 128.8, 128.3, 128.2, 122.3, 119.6, 119.3, 113.5, 78.9, 72.7,
59.5, 56.7, 55.4, 55.2. IR (KBr): ν 1755, 1720. MS: m/e 546,
512, 456, 411, 335, 293, 214, 160, 134, 91 (parent). Anal.
Calcd for C35H29N3O7: C, 69.64; H, 4.84; N, 6.96. Found: C,
69.73; H, 4.98; N, 6.81.
Syn t h esis of (3S*,4R*,4′R*,3′S*)-1-(p -An isyl)-4-[1-(p -
a n isyl)-3-isop r op yl-2-oxoa zetid in -4-yl]-3-isop r op yl-2-a ze-
tidin on e (1l) an d 1-(p-An isyl)-4-(N-(p-an isyl)azom eth in yl)-
3-isop r op yl-2-a zetid in on es 5d ,e. Ethyl isovaleriate (1.83
mL, 17.6 mmol) was added dropwise to a solution of LDA (17.6
mmol) in THF-hexanes cooled to -78 °C. After 15 min at
this temperature, a solution of diimine 3a (1.72 g, 8 mmol) in
THF (60 mL) was added, the bath was removed, and the
mixture was stirred for 2 h. The reaction was quenched with
H2O and diluted with Et2O (two or three times its original
(+)-(3R,4S,4′S,3′R)-1-(p-An isyl)-4-[3-a cetoxy-1-ben zyl-
2-oxoa zet id in -4-yl]-3-(b en zyloxy)-2-a zet id in on e (1h ).
Meth od B. Reaction time: 3 h. Yield: 0.38 g (75%). Color-
1
less oil. [R]D: +10.74 (c 4.70) H NMR: δ 2.01 (s, 3H), 3.33
(d, 1H, J ) 15.0 Hz), 3.80 (d, 1H, J ) 15.0 Hz), 3.82 (s, 3H),